Background Efavirenz and abacavir are components of recommended first-line regimens for HIV-1 infection. We used genome-wide genotyping and clinical data to explore genetic associations with virologic failure among patients randomized to efavirenz-containing or abacavir-containing regimens in AIDS Clinical Trials Group (ACTG) protocols. Participants and methods Virologic response and genome-wide genotype data were available from treatmentnaive patients randomized to efavirenz-containing (n = 1596) or abacavir-containing (n = 786) regimens in ACTG protocols 384, A5142, A5095, and A5202. Results Meta-analysis of association results across race/ethnic groups showed no genome-wide significant associations (P < 5x10(-8)) with virologic response for either efavirenz or abacavir. Our sample size provided 80% power to detect a genotype relative risk of 1.8 for efavirenz and 2.4 for abacavir. Analyses focused on CYP2B genotypes that define the lowest plasma efavirenz exposure stratum did not show associations nor did analysis limited to gene sets predicted to be relevant to efavirenz and abacavir disposition. Conclusion No single polymorphism is associated strongly with virologic failure with efavirenz-containing or abacavir-containing regimens. Analyses to better consider context, and that minimize confounding by nongenetic factors, may show associations not apparent here. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.