We evaluated the virological response in patients starting a regimen based on darunavir/ritonavir (DRV/r), which is currently the most widely used ritonavir-boosted protease inhibitor. Data from 206 drug-naïve and 327 PI-experienced patients starting DRV/r 600/100 mg twice daily (DRV600) or 800/100 mg once daily (DRV800) were examined. The probabilities of virological success (VS) and virological rebound (VR) were evaluated in survival analyses. Baseline DRV/r resistance and its evolution at failure were also examined. DRV600 was preferentially administered in patients with complex requirements (older age, higher viraemia, lower CD4 cell count and DRV/PI resistance) compared with DRV800. By 12 months, the probability of achieving VS was 93.2% and 84.3% in drug-naïve and PI-experienced patients, respectively. The higher the baseline viraemia, the longer was the time required to achieve VS, both in drug-naïve patients [>500 000 HIV-1 RNA copies/mL: median [interquartile range (IQR)] 6.1 (5.1-10.3) months; 100 000-500 000 copies/mL: median (IQR) 4.9 (3.8-6.1) months; <100 000 copies/mL: median (IQR) 3.9 (3.5-4.8) months; P < 0.001] and in PI-experienced patients [≥100 000 copies/mL: median (IQR) 7.2 (5.7-11.6) months; <100 000 copies/mL: median (IQR) 2.8 (2.4-3.3) months; P < 0.001]. In PI-experienced patients, the probability of VR was higher for higher viraemia levels (22.3% for ≥100 000 copies/ml vs. 9.7% for <100 000 copies/mL; P = 0.007). Baseline resistance did not affect the virological response. At failure, a high percentage of patients maintained virus susceptible to all PIs (drug-naïve: 95%; PI-experienced: 80%). Despite being used more often in patients with more complex requirements, DRV600 performed as well as DRV800. In clinical practice, use of DRV/r (with its flexible dosage) results in high rates of virological response. These data support the use of PI/r in patients whose characteristics require potent drugs with a high genetic barrier. © 2016 British HIV Association.