A case-cohort study was used to determine the effect of baseline nonnucleoside reverse-transcriptase inhibitor (NNRTI) resistance, as assessed by viral genotyping, on the response to efavirenz-containing regimens in AIDS Clinical Trials Group A5095. The sample included a random cohort of efavirenz-treated subjects plus unselected subjects who experienced virologic failure. Of 220 subjects in the random cohort, 57 (26%) had virologic failure. The prevalence of baseline NNRTI resistance was 5%. The risk of virologic failure for subjects with baseline NNRTI resistance was higher than that for subjects without such resistance (hazard ratio 2.27 [95% confidence interval], 1.15-4.49; P = .018). These results support resistance testing before starting antiretroviral therapy. © 2008 by the Infectious Diseases Society of America. All rights reserved.