Objectives To evaluate the virological efficacy, safety, tolerability and pharmacokinetics of a regimen containing 900/100 mg of ritonavir-boosted darunavir once daily in patients with antiretroviral experience but no darunavir resistance. Patients and methods An observational, prospective, multicentre study was conducted. Patients were included if 900/100 mg of darunavir/ritonavir once daily and at least one other active drug had been started due to virological failure, simplification or toxicity. Minimum follow-up was 24 weeks, or less if there was premature discontinuation of any drug or loss to follow-up. In a subgroup of patients, a complete 24 h pharmacokinetic study was performed by HPLC. Results One hundred and three patients (47 switch strategies, 56 early salvage therapies) were included. After 6 months, 85/103 (83%; 95% CI: 74%–89%) and 85/93 (91%; 95% CI: 84%–97%) patients had <50 copies/mL HIV-RNA by intention-to-treat and on-treatment analyses, respectively. The respective values were 42/47 (89%; 95% CI: 72%–96%) and 42/43 (98%; 95% CI: 88%–100%) in switch therapy, and 43/56 (77%; 95% CI: 64%–87%) and 43/50 (86%; 95% CI: 73%–94%) in salvage therapy. There was a significant increase in CD4 cell counts +73 cells/mm3 (95% CI: 43%–102%), P < 0.001. There were no interruptions due to rash or liver toxicity. Significant decreases in cholesterol and triglycerides were seen in patients with abnormal lipids at baseline. Ten patients discontinued antiretrovirals (5 were lost to follow-up and 5 due to side effects). Twenty-five patients were included in the pharmacokinetic study. All patients had trough plasma concentrations >0.05 μg/mL. Conclusions Darunavir/ritonavir at 900/100 mg once daily is highly effective, safe and well tolerated in treatment-experienced patients with no darunavir resistance, both in early salvage and switch strategies. Adequate drug plasma levels were achieved in all patients.