•Risk of in-hospital COVID-19 mortality in people living with HIV (PLWH) and the general population was assessed.•PLWH <65 years with clusters of differentiation (CD)4 ≤350 cells/mm3 are at higher risk of worse COVID-19 outcomes.•This risk is further increased in PLWH <65 years with CD4 count ≤200 cells/mm3.•The evidence was insufficient for PLWH aged ≥65 years.•PLWH with low CD4 counts should be prioritized for preventive interventions. We aimed to study whether people living with HIV (PLWH) are at higher risk of in-hospital COVID-19 mortality compared to the general population (GenPop). This was a retrospective study in 19 Italian centers (February 2020 to November 2022) including hospitalized PLWH and GenPop with SARS-CoV-2 infection. The main outcome was in-hospital mortality. Competing risk analyses by Fine-Gray regression model were used to estimate the association between in-hospital mortality and HIV status/age. A total of 7399 patients with COVID-19 were included, 239 (3.2%) PLWH, and 7160 (96.8%) GenPop. By day 40, in-hospital death occurred in 1283/7160 (17.9%) among GenPop and 34/239 (14.2%) among PLWH. After adjusting for potential confounders, compared to GenPop <65 years, a significantly higher risk of death was observed for GenPop ≥65 (adjusted subdistribution hazard ratio aSHR 1.79 95% CI 1.39-2.31), PLWH ≥65 (aSHR 2.16 95% CI 1.15-4.04), PLWH <65 with CD4 ≤200 (aSHR 9.69 95% CI 5.50-17.07) and PLWH <65 with CD4 201-350 (aSHR 4.37 95% CI 1.79-10.63), whereas no evidence for a difference for PLWH <65 with CD4 >350 (aSHR 1.11 95% CI 0.41-2.99). In PLWH aged <65 years a CD4 ≤350 rather than HIV itself seems the driver for the observed higher risk of in-hospital mortality. We cannot however rule out that HIV infection per se is the risk factor in those aged ≥65 years.