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Daily, oral use of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) for preexposure prophylaxis (PrEP) is an effective strategy to prevent acquisition of human immunodeficiency virus (HIV) infection. It is important to monitor PrEP uptake at the national level to increase our understanding of trends in its utilization, but national HIV surveillance data do not include PrEP uptake. Our objective was to develop feasible methods to estimate PrEP uptake and to estimate uptake each year among commercially insured persons during 2010–2014.We conducted a retrospective analysis of the 2010–2014 MarketScan database, a national sample of persons with commercial health insurance in the United States. We developed an algorithm to identify persons aged ≥16 years who were prescribed TDF-FTC for PrEP each year. We generated nationally representative estimates of prevalence of persons prescribed PrEP.We found a significantly increasing trend in the proportion of persons prescribed TDF-FTC for PrEP during the study period, with 417 users in 2010 and 9375 in 2014 (P < .001); 97% of PrEP users were male and 98% lived in metropolitan areas in 2014. During the study period, the numbers of women prescribed PrEP were low.Our analytic method provides the only feasible means to monitor PrEP uptake in the United States. Although a marked increasing trend in uptake was observed for men, the number of women who used PrEP remained very low during the study period. Interventions are needed to increase PrEP use by women at substantial risk of acquiring HIV infection.