OBJECTIVE To assess the effectiveness of simplification to a dual antiretroviral regimen containing a ritonavir-boosted protease inhibitor (PI/r) in treatment-experienced HIV-1-infected patients. METHODS Retrospective analysis of 131 HIV-1-infected patients on suppressive antiretroviral treatment (HIV-RNA <50 copies/mL) who switched to a maintenance dual antiretroviral regimen, containing a PI/r, in three hospitals in Spain. Virological failure was defined as confirmed HIV-RNA >50 copies/mL. The percentage of patients remaining free of therapeutic failure was estimated using the time-to-loss-of-therapeutic-response algorithm, by intent-to-treat analysis. RESULTS Median baseline characteristics of the patients were 14 years on antiretroviral therapy, five prior HAART regimens and 10 different drugs, 24 months on a suppressive regimen and 522 CD4+ cells/mL. Reasons for simplification to dual therapy were nucleoside reverse transcriptase inhibitor-related toxicity (46.6%), removal of lamivudine/emtricitabine due to resistance (16.8%), simplification from regimens containing a dual PI, enfuvirtide or tipranavir (20.6%) and simplification from other complex regimens (16.0%). Darunavir (58.0%), lopinavir (16.8%) or atazanavir (13.0%) were the preferred PIs, used in combination with tenofovir (50.4%), raltegravir (22.1%) or etravirine (12.2%). At the end of follow-up (median 14 months), 90.1% of patients remained free of therapeutic failure; corresponding data at treatment weeks 24, 48 and 96 were 93.6% (95% CI, 89.3-97.9), 90.9% (95% CI, 84.9-95.9) and 87.4% (95% CI, 80.7-94.1), respectively. Two (1.5%) patients had virological failure and 11 (8.4%) discontinued treatment due to side effects or were lost to follow-up. CONCLUSIONS Simplification to a dual-therapy regimen including a PI/r might be useful to enhance convenience and/or diminish toxicity in selected treatment-experienced patients.