Some individuals have higher efavirenz plasma concentrations during rifampin-containing tuberculosis (TB) therapy, contrary to the expected induction effect of rifampin. Among HIV-infected patients without (n = 38) and with TB on rifampin-containing therapy (n = 18), we tested the hypothesis that drug-gene interaction may explain the highly variable drug interactions. Two-way analysis of variance revealed a significant interaction between CYP2B6 516G→T polymorphism and rifampin-containing therapy, suggesting that efavirenz dose adjustment may need to be individualized on the basis of the patient's genotype.