© 2018 by American Society of Clinical Oncology. PURPOSE Conflicting evidence indicates that HIV seropositivity may influence the outcome of patients with hepatocellular carcinoma (HCC), a leading cause of mortality in people with HIV. We aimed to verify whether HIV affected the overall survival (OS) of patients with HCC, independent of treatment and geographic origin. PATIENTS AND METHODS We designed an international multicohort study of patients with HCC accrued from four continents who did not receive any anticancer treatment. We estimated the effect of HIV seropositivity on patients’ OS while accounting for common prognostic factors and demographic characteristics in uni- and multivariable models. RESULTS A total of 1,588 patients were recruited, 132 of whom were HIV positive. Most patients clustered within Barcelona Clinic Liver Cancer (BCLC) C or D criteria (n = 1,168 [74%]) and Child-Turcotte-Pugh (CTP) class B (median score, 7; interquartile range [IQR], 3). At HCC diagnosis, the majority of patients who were HIV-positive (n = 65 [64%]) had been on antiretrovirals for a median duration of 8.3 years (IQR, 8.59 years) and had median CD4 + cell counts of 256 (IQR, 284) with undetectable HIV RNA (n = 68 [52%]). OS decreased significantly throughout BCLC stages 0 to D (16, 12, 7.5, 3.1, and 3 months, respectively; P, .001). Median OS of patients who were HIV-positive was one half that of their HIV-uninfected counterparts (2.2 months [bootstrap 95% CI, 1.2 to 3.1 months] v 4.1 months [95% CI, 3.6 to 4.4 months]). In adjusted analyses, HIV seropositivity increased the hazard of death by 24% (P = .0333) independent of BCLC (P, .0001), CTP (P, .0001), a-fetoprotein (P, .0001), geographical origin (P, .0001), and male sex (P = .0016). Predictors of worse OS in patients who were HIV-positive included CTP (P = .0071) and a-fetoprotein (P, .0001). CONCLUSION Despite adequate antiretroviral treatment, HIV seropositivity is associated with decreased survival in HCC, independent of stage, anticancer treatment, and geographical origin. Mechanistic studies investigating the immunobiology of HIV-associated HCC are urgently required.