ABSTRACTTo investigate the prevalence, clinical manifestations, and risk factors of hypofibrinogenemia after tigecycline use, which can disrupt coagulation and potentially hinder antimicrobial therapy. This observational study was conducted from January to December 2021 at a tertiary general hospital in China. All patients over 18 years old who received tigecycline for more than 48 h were included. After treatment with tigecycline, patients were divided into two groups based on fibrinogen plasma concentrations of less than 2.0 g/L. Multivariable logistic regression was performed to identify risk factors for hypofibrinogenemia associated with tigecycline. A total of 50 patients (mean age 71.3 ± 20.2 years) were analyzed. The median duration of treatment was 8 days (range: 3 to 20 days). Among the 24 patients who developed hypofibrinogenemia, three gastrointestinal bleeding events were observed, and four of these patients required fibrinogen administration. We identified the total therapeutic dose (odds ratio (OR) = 15.28, 95% confidence interval (CI) 2.10–111.02, p = 0.01) and a baseline direct bilirubin level greater than 0.4 mg/dL (OR = 5.79, 95% CI 1.13–27.98, p = 0.04) as risk factors for tigecycline‐induced hypofibrinogenemia. Conversely, a baseline fibrinogen level (OR = 0.53, 95% CI 0.29–0.97, p = 0.04) appeared to be a protective factor. Healthcare professionals should be aware that the administration of tigecycline may be associated with hypofibrinogenemia and severe adverse reactions. Regular monitoring of coagulation is essential, particularly for patients with liver dysfunction, low baseline fibrinogen levels, elevated baseline direct bilirubin levels, or those receiving higher total therapeutic doses.