Switches from lopinavir/ritonavir (LPV/r) to either atazanavir/ritonavir (ATV/r) or unboosted ATV (ATV) are increasingly common in clinical practice, but data on outcome comparison between these two simplification strategies are very limited. METHODS Multicenter, observational, retrospective study. Data were collected from five Italian clinics. The objective of the study was to investigate the outcome of LPV/r simplification with ATV/r or ATV and to identify factors predicting virological rebound. Patients who switched from LPV/r to ATV/r or ATV with an HIV-RNA value<50 copies/mL at the time of switch and with at least one follow-up visit were included. We evaluated 468 patients (74.1% males), followed for a median (Q1-Q3) of 547 (305-788) days: 380 (81%) and 88 (19%) switched to ATV/r and to ATV, respectively. Virological rebound was detected in 78/468 (16.7%, 95% CI: 13.6 -20.3) patients [16/88 (18.2%, 95% CI: 11.4 -27.6) switched to ATV and 62/380 (16.3%, 95% CI: 12.9 -20.4) to ATV/r (p=0.638)]. Virological rebound was more frequent in patients who started LPV/r with HIV-RNA >30000 copies/mL (28% vs 6%, p=0.014). Replacing lopinavir/r with ATV or ATV/r yielded similar rates of virological rebound. Viral load at the initiation of lopinavir/r may be useful in driving the choice between ATV/r and ATV.