To investigate the relative magnitude and duration of impact of AIDS-defining events (ADEs) and non-AIDS serious adverse events (SAEs) on health-related quality of life (HRQoL) among patients with advanced HIV/AIDS. We use data from OPTIMA (OPTions In Management with Antiretrovirals), a multinational, randomized, open, control, clinical management trial of treatment strategies for patients with multidrug-resistant HIV and advanced immune disease. Longitudinal models were used to determine the effects of ADEs and SAEs on HRQoL across periods before, during, and after event onset. The Medical Outcomes Study HIV Health Survey (MOS-HIV) physical and mental health summary scores (MOS-PHS and MOS-MHS), EQ-5D, and the Health Utilities Index Mark 3 HRQoL measures were all assessed at regular follow-up intervals during the trial. ADEs occurred much less frequently than SAEs (n = 147 vs. n = 821) in the study sample population of 368 patients, during median follow-up of 3.96 years. Although both ADEs and SAEs had significant negative impacts on HRQoL, SAEs had at least as large an impact upon HRQoL as ADEs when both were included in a multivariate linear regression model, controlling for other covariates. However, the effect of ADEs on HRQoL was more persistent, with larger magnitude of effect across all instruments in time intervals further from the onset of the event. Non-AIDS SAEs occurring in patients with late-stage HIV/AIDS seem to have at least as important an immediate impact on patient HRQoL as ADEs; however, the impact of ADEs seems to be more persistent. Our findings call for a greater emphasis on the detection and active prevention of non-AIDS SAEs in patients with late-stage HIV/AIDS.