Drug overdose is a common cause of non-AIDS death among people with HIV and the leading cause of death for people who inject drugs. People with HIV are often exposed to opioid medications during their HIV care experience; others may continue to use illicit opioids despite their disease status. In either situation, there may be a heightened risk for nonfatal or fatal overdose. The potential mechanisms for this elevated risk remain controversial. We systematically reviewed the literature on the HIV–overdose association, meta-analyzed results, and investigated sources of heterogeneity, including study characteristics related to hypothesize biological, behavioral, and structural mechanisms of the association. Forty-six studies were reviewed, 24 of which measured HIV status serologically and provided data quantifying an association. Meta-analysis results showed that HIV seropositivity was associated with an increased risk of overdose mortality (pooled risk ratio 1.74, 95% confidence interval 1.45, 2.09), although the effect was heterogeneous (Q = 80.3, P < 0.01, I2 = 71%). The wide variability in study designs and aims limited our ability to detect potentially important sources of heterogeneity. Causal mechanisms considered in the literature focused primarily on biological and behavioral factors, although evidence suggests structural or environmental factors may help explain the greater risk of overdose among HIV-infected drug users. Gaps in the literature for future research and prevention efforts as well as recommendations that follow from these findings are discussed.