The growing numbers of HIV-infected patients requiring second-line antiretroviral therapy (ART) in Vietnam make essential the evaluation of treatment efficacy to guide treatment strategies.We evaluated all patients aged ≥15 years who initiated second-line ART after documented failure of first-line therapy at the Hospital for Tropical Diseases in Ho Chi Minh City. The primary outcome was time from second-line ART initiation to death, or to a new or reoccurrence of a WHO-defined immunological or clinical failure event, whichever occurred first. Risks of treatment failure and death were evaluated using Cox proportional hazards modeling.Data from 326 of 373 patients initiating second-line ART between November 2006 and August 2011 were included in this analysis. The median age was 32 years (IQR: 28-36). Eighty one percent were men. The median CD4 count was 44 cells/μL (IQR: 16-84). During a median follow-up of 29 months (IQR: 15-44), 60 (18.4%) patients experienced treatment failure, including 12 immunological failures, 4 WHO stage IV AIDS events, and 44 deaths (13.5%). Sixty percent of deaths occurred during the first 6-12 months. The Kaplan-Meier estimates of treatment failure after 1, 2, 3, and 4 years were 13.1% (95% CI: 9.2-16.8), 18.6% (95% CI: 14.0-23.1), 20.4% (95% CI: 15.4-25.1), and 22.8% (95% CI: 17.2-28.1), respectively. Older age, history of injection drug use, lower CD4 count, medication adherence <95%, and previous protease inhibitor use independently predicted treatment failure.While treatment efficacy was similar to that reported from other resource-limited settings, mortality was higher. Early deaths may be averted by prioritizing second-line therapy for those with lower CD4 counts and by improving treatment adherence support.