We reported quality of life (QOL) and adherence in HIV-infected children after simplifying the antiretroviral regimen by switching to lopinavir/ritonavir monotherapy (mLPV/r). HIV-infected children with HIV-RNA <50 copies/ml while using second-line double boosted protease inhibitors were switched to mLPV/r. Primary caregivers completed PACTG QOL questionnaires at weeks 0, 48, 96, and 144. Adherence by pill count was performed at every visit. Thirty-eight pretreated HIV-infected Thai children were enrolled. The median (IQR) age was 11.5 (10.2-13.2) years and 53% were female. At enrollment, 34 used LPV/r+saquinavir and four used LPV/r+indinavir. The median (IQR) CD4% was 27 (23-30)%. At week 144, QOL scores were similar to baseline for all domains. A transient increase in the symptoms domain score was seen at week 96 (p=0.01), whereas the physical resilience domain score was decreased at weeks 48 and 96 (both p<0.05). Despite the mean number of pills decreasing from 7.9 pills/day before and 3.7 pills/day after mLPV/r (p<0.001), there were no differences over time in adherence rates by pill count and proportion of children with poor adherence (all p>0.05). Our study did not demonstrate improvement of QOL scores and adherence rates by pill count in pretreated HIV-infected children after simplification of the antiretroviral regimen to lopinavir/ritonavir monotherapy.