OBJECTIVE: We evaluated improvement of quality of life (QoL) after one year of secondline antiretroviral therapy (ART) use in resource-limited settings (RLS) among adult men and women, comparing two randomized treatment arms. DESIGN: ACTG A5273 was a randomized clinical trial of second-line ART comparing lopinavir/ritonavir (LPV/r) + raltegravir (RAL) with LPV/r + nucleos(t)ide reverse transcriptase inhibitors (NRTIs) in participants failing a non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimen at 15 sites in 9 RLS. Participants completed the ACTG SF-21 which has 8 QoL domains with a standard score ranging from 0 (worst) to 100 (best). METHODS: Differences in QoL by randomized arm, as well as by demographic and clinical variables, were evaluated by regression models for baseline and week 48 QoL scores fitted using the generalized estimating equations method (GEE). RESULTS: 512 individuals (49% male, median age 39 years) were included. 512 and 492 participants had QoL assessments at baseline and week 48, respectively. QoL improved significantly from week 0 to 48 (p<0.001 for all domains). There was no significant difference between treatment arms for any domain. Individuals with higher VL and lower CD4 at baseline had lower mean QoL at baseline but larger improvements such that mean QoL was similar at week 48. CONCLUSIONS: Improvements in QoL were similar after starting second-line ART of LPV/r combined with either RAL or NRTIs in RLS. QoL scores at baseline were lower among participants with worse disease status prior to starting second-line, but after one year similar QoL scores were achieved.