© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. Background. None of the 3 regimens tested in the VOICE study showed protection against human immunodeficiency virus (HIV) infection in intent-to-treat analyses. Plasma tenofovir concentrations demonstrated poor adherence to the study product among study subjects. Statistical analyses to explore the causal treatment effect on the prevention of HIV infection among adherent individuals are needed. Methods. We developed an analytical strategy to evaluate whether conventional covariate adjustment removes confounding and thereby reveals a prevention effect among adherent individuals. We applied this strategy to the VOICE study, using 2 dichotomized proxy measures of product use: detection of tenofovir in plasma at least once during follow-up and detection of tenofovir in plasma at the 3-month follow-up visit. Results. After adjustment for a set of baseline predictors of the risk of HIV transmission, the confounding associated with comparison of adherent individuals in the tenofovir gel arm to placebo recipients was nearly eliminated. The relative risk for a prevention effect among those ever having tenofovir detected was 0.53 (P =. 038); the relative risk among those having tenofovir detected at 3 months was 0.40 (P =. 045). Conclusions. A novel regression approach was proposed for causal as-treated analyses in the VOICE study. While intent-to-treat analyses yield null results, this exploratory approach presented evidence suggesting a prevention effect among gel users.