To compare outcomes of nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine or efavirenz versus abacavir-based regimens with a backbone of zidovudine and lamivudine as initial therapy of treatment-naive adults with HIV-1 infection in routine clinical care. All patients starting their first antiretroviral therapy with any of the studied regimens from January 1999 to December 2002 were included in the analysis. Rates of viral suppression (HIV-RNA below 50 copies/mL) and discontinuation of any component of the regimen were compared at 48 weeks. Fifty-one patients started with one of the two NNRTI-based regimens and 49 started with the triple nucleoside regimen (3-NRTI). After 48 weeks, more patients in the NNRTI regimens (76.5%) than in the 3-NRTI (51.1%) regimen achieved a HIV-1 RNA level below the limit of detection (<1.7 log10 copies/mL; p = .008). Time to change the antiretroviral regimen was shorter with 3-NRTI (median [range]: 234 [139-329] days) than with NNRTI (346 [0-756] days) (p = .0901). More withdrawals related to drug toxicity or intolerance occurred with the 3-NRTI-based regimen. In a routine clinical care setting, initial antiretroviral treatment with an NNRTI (nevirapine or efavirenz) plus zidovudine and lamivudine was virologically superior and safer than a 3-NRTI therapy (abacavir with the same NRTI backbone).