INTRODUCTION: Hospitalized people living with HIV (PLWH) experienced extremely high mortality rates in the first year after an index hospitalization in the pre-Dolutegravir (DTG) era. We conducted a multi-center study in Mwanza, Tanzania to (1) describe causes of hospitalization for PLWH on DTG; (2) determine in-hospital and 3-month post-hospital mortality; (3) examine factors associated with overall mortality; and (4) determine changes in trends and predictors of mortality pre- and post-DTG era. METHODS: Between August 2020 and February 2021, hospitalized PLWH on dolutegravir-based antiretroviral therapy were enrolled and followed for three months after hospitalization. The primary outcome was mortality within 3-months of hospitalization. Cox regression analysis was used to calculate hazard ratios to identify predictors of mortality. RESULTS: Of the 154 enrolled patients, the median [interquartile range] age was 42 [33-50] years and 57% were female. Suspected immune reconstitution inflammatory syndrome (IRIS) and antiretroviral therapy (ART) non-adherence leading to an HIV-associated admission were common. The overall all-cause mortality was 42%. Male sex, using DTG-based regimen for < 3 months, diagnosis of suspected IRIS, diagnosis of ART side effect, advanced WHO clinical stage, CD4 count < 200 cells/mm3, hemoglobin level 7-11.9 gm/dl and hemoglobin level < 7 gm/dl were all independent risk factors for death. CONCLUSION: In conclusion, the mortality rate of hospitalized PLWH in Africa remains high in the DTG era. Clinical trials are urgently needed to test novel interventions for improving survival in this high-risk group. In the meantime, hospital clinicians should be aware of the very high mortality among PLWH with IRIS and those with ART side effect to ensure that all possible diagnostic and therapeutic options are explored.