Background The intense use of antiretroviral therapy (ART) has reduced morbidity and mortality of HIV infection. In Brazil, the specific contribution of diseases related to HIV infection leading to hospital admission and readmission is not well known. Aims The study aimed to determine the clinico-epidemiological profile, 30-day readmission rate, and factors associated with this outcome in a cohort of adults with HIV infection in southern Brazil. Methods Unicentric retrospective cohort, with data collection through the review of medical records and databases. Results We analyzed 574 index hospitalizations and 451 individuals. Of these, 57.6% were men and the mean (±SD) age was 42.2 ± 12.3 years. Only 43.4% used ART regularly and low CD4 count and high frequency of detectable viral load were observed. HIV/AIDS-related diseases were identified in 55.2%, and tuberculosis was the most frequent etiology leading to index hospitalization. We found a 30-day readmission rate of 11.5% and hospitalization for HIV/AIDS-related illness was associated with a higher risk for the outcome. Conclusions These findings highlight the need to expand resources for prevention, early diagnosis, retention, and treatment of people living with HIV in the region to reduce HIV/AIDS-associated diseases and possibly minimize consequent hospital readmission of these individuals.