The effectiveness of etravirine has not been thoroughly investigated in routine clinical practice, where adherence rates and the heterogeneous nature of patients differ from the clinical trial setting. We evaluated the effectiveness of rescue regimens containing etravirine and the factors associated with treatment response. Multicenter retrospective cohort of all consecutive patients was recruited in a routine clinical practice setting. Patients were taking rescue regimens containing etravirine plus an optimized background regimen. The primary endpoint was the percentage of patients with HIV-1 RNA <50 copies/ml at week 48. The secondary endpoints were those factors associated with treatment response to etravirine. Endpoints were evaluated using univariate and multivariate analysis. A total of 122 patients were included with a median viral load of 11,938 (1055-55,500) copies/ml at baseline. The most frequent drugs in the backbone were darunavir/ritonavir in 98 (80.3%) patients and raltegravir in 76 (62.3%). In the full dataset analysis, 73% (89/122; 95% CI, 64-81%) of patients responded to treatment at week 48; in the on-treatment analysis, 82% (89/109; 95% CI, 71-87%) responded. The factors associated with treatment failure to etravirine [HR (95% CI)] were baseline CD4+ T cell count <200 cells/mm3 [2.45 (1.17-5.16)] and use of raltegravir [0.47 (0.22-0.99)] and darunavir [0.45 (0.21-0.98)] as backbone drugs. Skin rash was the only adverse event directly related to etravirine and led to withdrawal in three patients (2.5%). In routine clinical practice, rescue ETR-containing regimens are well tolerated and achieve rates of virological suppression higher than those observed in its pivotal clinical trials, especially when combined with darunavir and raltegravir. © 2011, Mary Ann Liebert, Inc.