Objective: To evaluate the impact of AIDS-defining events (ADE) on long-term mortality of HIV positive individuals on antiretroviral therapy (ART), a retrospective HIV/AIDS treatment cohort study performed in Southwestern China. Methods: The retrospective cohort was conducted among 6757 HIV/AIDS patients on ART (2NRTIs + 1NNRTI, 2NRTIs + 1PI and Single or two drugs) recruited in Guigang city, Guangxi, China, from January 2004 to December 2018. Participants were divided into ADE and non-ADE groups, and were followed-up every six months to observe treatment outcomes. Comparison of mortality between groups was performed using the log-rank test and Kaplan-Meier analysis. Cox proportional hazard regression was used to explore the risk factors of mortality. 1:1 propensity score matching (PSM) was used to balance confounding factors and adjust the mortality risk. Results: Of 6757 participants with 29,096.06 person-years of follow-up, 16.86% (1139/6757) belonged to ADE group while the others (83.14%) belonged to the non-ADE group. The most common cause of death by ADE was disseminated mycosis (31.65%), followed by recurrent severe bacterial pneumonia (28.48%), herpes zoster (17.72%), and extra-pulmonary tuberculosis (8.86%). The mortality of the ADE group was significantly higher than that of the non-ADE group [3.45/100 person-years (95% CI 2.92-3.97) vs. 2.34/100 person-years (95% CI 2.15-2.52), P<0.001]. The death risk of the ADE group was also higher than that of the non-ADE group [adjusted hazard ratio (aHR) = 1.291, 95% CI 1.061-1.571, P = 0.011], which was confirmed by PSM analysis (aHR = 1.581, 95% CI 1.192-2.099, P = 0.002). Cox analysis indicated that ADE, older age, male gender, previous non-use of cotrimoxazole, advanced WHO clinical stage, and low baseline CD4 + cell count were the risk factors for death. Conclusions: Even on ART, the mortality risk of HIV positive individuals with ADE was higher than those without ADE. Active testing, earlier diagnosis, and timely therapy with ART may reduce the death risk of ADE.