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. 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. 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, 89.397.9), 90.9 (95 CI, 84.995.9) and 87.4 (95 CI, 80.794.1), respectively. Two (1.5) patients had virological failure and 11 (8.4) discontinued treatment due to side effects or were lost to follow-up. 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.