The potency of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and efavirenz in patients with higher viral loads (VLs) or low CD4 cell counts remains uncertain. Virologic failure and changes in CD4 count in relation to pretreatment VL and CD4 count were evaluated in treatment-naive patients randomized to treatment groups that received 2 or 3 NRTI swith efavirenz. Over 3 years, the risk of virologic failure was not significantly different among subgroups categorized according to pretreatment VL or CD4 count. No significant differences among subgroups were observed for CD4 count changes, except in patients with high pretreatment VL. There were no significant differences among subgroups with respect to treatment responses. These results demonstrate the potency of efavirenz-containing regimens across a spectrum of pretreatment VLs and CD4 counts. Trials registration. © 2008 by the Infectious Diseases Society of America. All rights reserved.