Currently, comparative data able to define the potency of boosted versus unboosted atazanavir in highly pretreated HIV-infected patients are limited. Specifically, in clinical practice it is very important to establish whether atazanavir-boosting with ritonavir warrants potency and efficacy that overcome the profile of unboosted drug. For this reason, our goal was to evaluate viro-immunologic determinants of response to atazanavir, in unboosted ATV400 or boosted ATV300/r formulation, from baseline to week 48 in highly pretreated HIV-infected patients enrolled in a prospective observational Italian study. Data from 354 patients included in an atazanavir "Early Access Program" (AI424-900) with baseline viremia 500 copies per milliliter or more and with an available virologic follow-up were examined using as-treated analysis. Of these, 200 (56.5%) and 154 (43.5%), respectively, received regimens containing ATV300/r or ATV400. Virologic success (VS) was defined as reaching viremia of less than 500 copies per milliliter during follow-up. Estimated median time to VS was 8 weeks in the ATV300/r group and 13 weeks in the ATV400 group. Proportion of patients achieving VS was higher in the ATV300/r group than in ATV400 group at week 12 (66% versus 47%), as well as at week 48 (86% versus 64%). At multivariate Cox regression, receiving ATV300/r dosing was independently associated with increased probability of achieving VS [adjusted hazard ratio (AHR): 1.57; 95% confidence interval (CI): 1.19-2.06]. Conversely, CDC stage C, higher baseline viral load, and more experience with protease inhibitors (PIs) were associated with poorer virologic response. In an unselected population of highly pretreated HIV-infected individuals, receiving atazanavir as part of antiretroviral regimen results in effective virologic response and immunologic recovery. The antiviral efficacy of atazanavir is greater when boosted with low-dose ritonavir.