SummaryDespite significant reductions in morbidity and mortality secondary to availability of effective combination anti‐retroviral therapy (cART), human immunodeficiency virus (HIV) infection still accounts for 1.5 million deaths annually. The majority of deaths occur in sub‐SaharanAfrica where rates of opportunistic co‐infections are disproportionately high. In this review, we discuss the immunopathogenesis of five common infections that cause significant morbidity inHIV‐infected patients globally. These include co‐infection withMycobacterium tuberculosis,Cryptococcus neoformans, hepatitis B virus, hepatitis C virus, andPlasmodium falciparum. Specifically, we review the natural history of each co‐infection in the setting ofHIV, the specific immune defects induced byHIV, the effects ofcARTon the immune response to the co‐infection, the pathogenesis of immune restoration disease (IRD) associated with each infection, and advances in the areas of prevention of each co‐infection via vaccination. Finally, we discuss the opportunities and gaps in knowledge for future research.