We compared immunovirological outcomes and toxicities of HAART regimens including LPV/r and IDV/r in antiretroviral naïve HIV-1 patients. We retrospectively selected 55 patients starting LPV/r and 52 starting IDV/r as first-line HAART. Immunovirological and metabolic parameters were recorded at baseline and every 3 months as were side effects, AIDS-defining events and deaths. Demographic characteristics and NRTIs included in the regimens were comparable. Both groups reached undetectable HIV-RNA plasma viremia from third month and maintained during follow-up. However, patients receiving IDV/r had a lower probability to obtain virological success (RH: 0.46). Patients receiving IDV/r patients showed a greater increase of total cholesterol (P = 0.01). Three patients on LPV/r and 21 on IDV/r discontinued the drug for toxicity, leading to a 8.40 higher risk of discontinuation in the latter group. In our clinical setting IDV/r showed to be less effective and more toxic than LPV/RTV as first-line HAART.