Despite having demonstrated noninferior efficacy against atazanavir/ritonavir plus coformulated tenofovir/emtricitabine (cTDF/FTC), the combination of nevirapine plus cTDF/FTC is not included among preferred regimens in some international guidelines. This combination is frequently used in Spain. We analyzed its effectiveness and safety as first-line therapy in a routine clinical practice. A retrospective, multicenter study was performed in treatment-naive HIV-1-infected subjects who started nevirapine plus cTDF/FTC as first-line therapy according to the nevirapine CD4 + cell count threshold. The primary endpoint was the proportion of subjects with plasma HIV-1 RNA <50 copies/ml at week 48. We included 123 subjects starting the regimen from 2005 to 2008. The median age was 41.0 years, the median baseline CD4 + cell count was 215 cells/μl, the median plasma viral load (VL) was 4.83 log 10 copies/ml, and 22% had hepatitis C coinfection. At week 48, 96 subjects (78%; 95% CI: 69.9-84.4) had a VL <50 copies/ml in an ITT analysis, and the median rise in the CD4 + cell count was 118 cells/μl. Virological failure was observed in 6.5% (8/123) of subjects, all them before week 24 and related to poor adherence. There was no relationship between virological failure and baseline CD4 + cell count or VL. Ten percent (13/123) of the subjects discontinued the treatment due to adverse events. There was a significant decrease in total/HDL-cholesterol ratio (p=0.03) with an increase in HDL-cholesterol (p=0.01) over 48 weeks. The combination of nevirapine plus cTDF/FTC showed a high virological efficacy without unexpected toxicities as a first-line treatment in a routine clinical practice. © Copyright 2012, Mary Ann Liebert, Inc.