Introduction: Pre-exposure prophylaxis (PrEP) may be an important safer conception strategy for HIV-1-uninfected women with HIV-1-infected partners. Understanding medication adherence in this population may inform whether PrEP is a feasible safer conception strategy. Methods: We evaluated predictors of pregnancy and adherence to study medication among HIV-1-uninfected women enrolled in a randomized placebo-controlled trial of PrEP among African HIV-1-serodiscordant couples. Participants were counseled on HIV-1 risk reduction, contraception, and adherence and tested for pregnancy at monthly study visits. Pill counts of dispensed drug were performed and, at a subset of visits, plasma was collected to measure active drug concentration. Results: Among 1785 women, pregnancy incidence was 10.2 per 100 person-years. Younger age, not using contraception, having an additional sexual partner, and reporting unprotected sex were associated with increased likelihood of pregnancy. Monthly clinic pill counts estimated that women experiencing pregnancy took 97% of prescribed doses overall, with at least 80% pill adherence for 98% of study months, and no difference in adherence in the periconception period compared with previous periods (P = 0.98). Tenofovir was detected in plasma at 71% of visits where pregnancy was discovered. By multiple measures, adherence was similar for women experiencing and not experiencing pregnancy (P 0.1). Conclusions: In this clinical trial of PrEP, pregnancy incidence was 10% per year despite excellent access to effective contraception. Women experiencing pregnancy had high medication adherence, suggesting that PrEP may be an acceptable and feasible safer conception strategy for HIV-1-uninfected women with HIV-1-serodiscordant partners. © 2014 by Lippincott Williams & Wilkins.