OBJECTIVES: To explore 48 week safety and efficacy of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients with virological suppression on a stable atazanavir/ritonavir-based standard triple regimen. METHODS: This was a single-arm pilot study, enrolling 40 patients on atazanavir/ritonavir + two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), without previous treatment failure, with HIV-RNA <50 copies/mL for >3 months and CD4 >200 cells/mm(3). At baseline, patients were switched to 300/100 mg of atazanavir/ritonavir + 300 mg of lamivudine once daily. Laboratory parameters, atazanavir plasma levels, self-reported adherence, quality of life, neurocognitive performance, bone composition and body fat distribution were monitored. Virological failure was defined as HIV-RNA >50 copies/mL on two consecutive determinations or a single level >1000 copies/mL. RESULTS: After 48 weeks, 4/40 (10%) regimen discontinuations occurred: 1 death (brain haemorrhage), 1 study withdrawal (inadequate atazanavir plasma levels), 1 re-induction with two NRTIs due to pregnancy and 1 virological failure without development of resistance. Seven moderate to severe adverse events were recorded (including four renal colics, possibly treatment-related) in six patients. At week 48, increases in total (mean change +17 mg/dL, P = 0.001), high-density lipoprotein (+6 mg/dL, P < 0.001) and low-density lipoprotein (+8 mg/dL, P = 0.052) cholesterol were observed. The glomerular filtration rate improved (+7 mL/min/1.73 m(2), P < 0.001), as did scores exploring self-reported physical and mental health (+11, P = 0.009 and +13, P < 0.001 on a 0-100 scale), neuropsychological performance (-1 pathological task, P = 0.002) and total bone mineral density (+0.03 g/cm(2), P = 0.026). There were no significant changes in CD4 cell count, bilirubin, atazanavir plasma levels, adherence and body fat distribution over time. CONCLUSIONS: Simplification to atazanavir/ritonavir + lamivudine was apparently safe and associated with rare virological failure, without resistance selection. This strategy deserves further investigation in a randomized trial.