To report long-term data on safety and effectiveness of antiretroviral regimens, including nevirapine. HIV-1- infected patients who received nevirapine-based approaches for at least 4 years were identified in the databases of five centers and included in a retrospective cohort study. Data collected included plasma HIV-RNA (viral load) and CD4+ Tcell counts, lipid and liver function tests, at baseline, 2-year and > 4-year time points. Hepatitis C virus (HCV) coinfection, adverse events, and reasons for using nevirapine were also recorded. Two hundred and twenty-nine patients (139 males/90 females) were included. The mean age was 37 years (range 20-59). Most patients (n = 124; 54%) were former intravenous drug users. One hundred and thirty-five of the patients (59%) were coinfected with HCV. Median time on nevirapine was 72.6 months. The main reasons for nevirapine use included: second- or third-line therapy (39%), simplification of therapy (29%), first-line therapy (18%) and efavirenz intolerance (9%). LDL cholesterol and triglycerides decreased during the > 4-year follow-up (135 mg/dl to 109 mg/dl, p = 0.04; and 216 mg/dl to 153 mg/dl, p < 0.01, respectively), and HDL cholesterol increased from 48 mg/dl at baseline to 62 mg/dl (p < 0.01). Liver enzymes remained without significant changes during follow-up. The reported follow-up pattern of laboratory tests was also found in the subset of HCV-coinfected patients, where men and women were compared and patients with a CD4+ cell count cutoff value of 250/mm3 were stratified. Mean CD4+ T-cell counts increased from 439/mm3 at baseline to 628/mm3 at the last available visit (p < 0.001). Ninety-four per cent (172 out of 184) of patients who remained on nevirapine-based therapy at last visit maintained viral load values below the limit of detection ( < 50 copies/ml). Throughout the follow-up nevirapine was stopped or withdrawn in 43 patients due to virological failure (n = 17), toxicity (n = 5), therapy interruption (n = 3), death (n = 2), dyslipidemia (n = 1), simplification (n = 1) or unknown reasons (n = 14). Adverse events were reported in 40 patients but none was directly attributed to nevirapine. Nevirapine-based antiretroviral therapy provides sustained immunological and virological effectiveness over a more than 4-year treatment period as well as a beneficial lipid metabolic profile and a favorable safety profile, even in HCV-coinfected patients and women with CD4+ cell counts above 250/mm3. The study data support a nevirapine-based approach as a suitable long-term strategy in the HIV-1-infected population.