The non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz (EFV) and nevirapine (NVP) taken in combination with nucleoside reverse transcriptase inhibitors (NRTIs) have both shown to be just as highly effective as protease inhibitors (PIs) in reducing viral load in patients infected with HIV. Our study compares the performance of these two NNRTIs with each other. This was a non-randomized, prospective, two-arm, multi-centre trial. We evaluated all patients with an EFV- or NVP-containing antiretroviral regimen. The primary endpoint was the difference in success rates defined as a viral load of </=50 copies/mL at week 48. chi(2)-tests were used for naïve and pretreated patients using intention-to-treat (ITT) and on-treatment analysis. As secondary endpoints, a viral load of </=500 copies/mL and CD4 count at week 48 for naïve patients were evaluated. A Cox regression was used to adjust for prespecified covariates. We included 662 patients (NVP 337, EFV 325). The difference in success rates in the ITT analysis was 4.5% ( -11.5%, 19.0%), P=0.578. Pretreated patients with a triple therapy show a difference of 10.1 (-0.3, 20.6), P=0.056. Non-significant results appeared for all secondary analyses. In this trial, no difference between EFV and NVP in combination with NRTI backbone therapy can be shown, regarding viral load. Further randomized studies are necessary to evaluate possible differences.