OBJECTIVES: This article aims to elucidate the relationship between antiretroviral (ARV) medication changes and all-cause mortality using a total of 368 patients recruited from the United States (78%), United Kingdom (11%), and Canada (11%). METHODS: Data sources included demographic characteristics, ARV treatment history and modifications, and clinical biomarker data from the completed OPTions In Management with Antiretrovirals clinical trial. Descriptive analysis and graphical trajectory representation of ARV drug modifications and biomarker changes were undertaken. Three hypotheses aimed at assessing the impact of ARV modification parameters on clinical outcomes were tested. Kaplan-Meier survival techniques as well as Cox proportional hazard regression models were employed. RESULTS: Results from the analyses suggest that (1) switching therapy strategy from an intensified ARV regimen to a less intense one or vice versa, (2) having a moderate number (up to 2) of ARV drug changes per 6 months, and (3) changes based on clinical/HIV-related reasons or nonclinical reasons compared to ARV drug regimen changes due to clinical non-HIV reasons improved survival. CONCLUSION: Modifications in the ARV regimens of HIV-infected patients with multidrug resistance are associated with improved survival.