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To describe the use of second line protease-inhibitor (PI) regimens across Europe and to determine factors associated with virological and immunological response.Analysis of data from 984 patients with a median follow-up of 21 months enrolled in EuroSIDA. Patients started their second PI-containing regimen at least 16 weeks after starting the first PI-containing regimen and with viral load > 1000 copies/ml.Virological response was defined as a viral load < 500 copies/ml and immunological response as an increase of 50 × 106/l or more in CD4 lymphocyte count.The median CD4 cell count at starting the second PI was 171 × 106 cells/l; viral load was 4.45 log copies/ml. As a second PI regimen, 45% were using a dual PI, while of those on one PI, indinavir (42%) and nelfinavir (34%) were most common. In multivariate Cox models, a higher viral load at starting the second PI [relative hazard (RH), 0.67 per 1 log higher; 95% confidence interval (CI), 0.58–0.77;P < 0.0001) and a lower CD4 cell count (RH, 1.15 per 50% higher; 95% CI, 1.06–1.26;P = 0.0014) were associated with a reduced probability of virological response. Those who had achieved viral suppression on the first PI-regimen were more likely to respond to the second (RH, 1.65; 95% CI, 1.30–2.10;P < 0.0001) as were those who added one or two new nucleosides to their second PI.Patients who initiate a second PI regimen at lower viral load, higher CD4 cell count or who added new nucleosides tended to be more likely to achieve a viral load < 500 copies/ml. The roles of cross-resistance and adherence in response to second-line regimens needs further investigation.