To summarize available data and contribute to a broader understanding of the global incidence and prevalence of acquired factor X deficiency. A comprehensive review of English-language publications from PubMed and Embase was conducted. The majority of publications on acquired factor X deficiency were associated with light-chain (AL) amyloidosis. Therefore, this review is structured to assess publications reporting on (1) acquired factor X deficiency associated with AL amyloidosis or (2) acquired factor X deficiency associated with other causes. The literature includes case reports, case-series, and limited population-based reports of the epidemiology of acquired factor X deficiency. Though no definitive global incidence or prevalence estimates for AL-amyloidosis-associated acquired factor X deficiency were identified, the finding that roughly 6–14% of patients with AL amyloidosis have factor X activity levels below 45–50% of normal highlights the rarity of acquired factor X deficiency associated with AL-amyloidosis. Indeed, AL amyloidosis itself is a rare disorder with an estimated annual incidence of ∼10 cases per million population. Only case reports were available to inform the epidemiology of acquired factor X deficiency not associated with AL amyloidosis. We identified 35 cases from 29 papers published from around the globe. At least 25 of those patients experienced a bleeding event, with factor X activity levels ranging from <1% to 39%. More population-based data are needed to understand the epidemiology of acquired factor X deficiency; however, the limited data seem to indicate this condition is quite rare. The variation across papers in thresholds used to define deficiency highlights the need for a standardized definition to better inform drug development, resource allocation, and regulatory decision-making. What is the context?Factor X is a protein in the blood that helps with clotting. Factor X deficiency is a rare condition that could cause dangerous bleeding episodes.People can be born with this deficiency (hereditary factor X deficiency) or they can experience it later in life, often in association with another disease or exposure (acquired factor X deficiency).Little is known about how many people worldwide have acquired factor X deficiency. Factor X is a protein in the blood that helps with clotting. Factor X deficiency is a rare condition that could cause dangerous bleeding episodes. People can be born with this deficiency (hereditary factor X deficiency) or they can experience it later in life, often in association with another disease or exposure (acquired factor X deficiency). Little is known about how many people worldwide have acquired factor X deficiency. What is new?This paper is a literature review about two groups of people with acquired factor X deficiency – those who have low levels of factor X because they also have a condition called light-chain amyloidosis (AL amyloidosis) and those who have low levels of factor X for some other reason.AL amyloidosis is itself quite rare, and only about 6–14% of people with AL amyloidosis have factor X activity levels below 45–50% of normal.Very little data are published about people with low factor X activity levels due to reasons other than AL amyloidosis. In fact, this paper found that only case reports were available to describe acquired factor X deficiency in patients without AL amyloidosis. The case reports describe only 35 cases from around the globe.Many patients with acquired factor X deficiency experienced a bleeding event, and bleeding occurred at factor X activity levels as low as <1% and as high as 39% of normal. This paper is a literature review about two groups of people with acquired factor X deficiency – those who have low levels of factor X because they also have a condition called light-chain amyloidosis (AL amyloidosis) and those who have low levels of factor X for some other reason. AL amyloidosis is itself quite rare, and only about 6–14% of people with AL amyloidosis have factor X activity levels below 45–50% of normal. Very little data are published about people with low factor X activity levels due to reasons other than AL amyloidosis. In fact, this paper found that only case reports were available to describe acquired factor X deficiency in patients without AL amyloidosis. The case reports describe only 35 cases from around the globe. Many patients with acquired factor X deficiency experienced a bleeding event, and bleeding occurred at factor X activity levels as low as <1% and as high as 39% of normal. What is the impact?This paper collects all of the available information about acquired factor X deficiency into one place. It demonstrates not only how rare the condition appears to be, but also that more research is needed. Larger, more representative studies that look at entire populations are needed to better understand how many people truly have acquired factor X deficiency.There also needs to be a standard way to define what levels of factor X should be considered as a ‘deficiency’ that leads to excessive bleeding.This definition could help improve treatments, inform drug development, resource allocation, and regulatory decision-making. This paper collects all of the available information about acquired factor X deficiency into one place. It demonstrates not only how rare the condition appears to be, but also that more research is needed. Larger, more representative studies that look at entire populations are needed to better understand how many people truly have acquired factor X deficiency. There also needs to be a standard way to define what levels of factor X should be considered as a ‘deficiency’ that leads to excessive bleeding. This definition could help improve treatments, inform drug development, resource allocation, and regulatory decision-making.