An estimated 56,000 human immunodeficiency virus (HIV) infections occur each year in the United States. Men who have sex with men (MSM) account for 53% of the estimated incident infections, and surveillance data suggest that the annual number of new HIV infections among MSM has been rising since the mid-1990s. Strategies for reducing acquisition of HIV infection by MSM have included 1) expanded HIV testing so that infected persons can be treated and their risk for transmitting infection minimized; 2) individual, small-group, and community-level behavioral interventions to reduce risk behaviors; 3) promotion of condom use; 4) detection and treatment of sexually transmitted infections; and 5) mental health and substance abuse counseling when needed. On November 23, 2010, investigators for the Pre-Exposure Prophylaxis Initiative (iPrEX) study announced results from a multinational, randomized, double-blind, placebo-controlled, phase III clinical trial of daily oral antiretrovirals (tenofovir disoproxil fumarate [TDF] and emtricitabine [FTC]) to prevent acquisition of HIV infection among uninfected but exposed MSM. This report provides interim guidance to health-care providers based on the reported results of that trial, which indicated that TDF plus FTC taken orally once a day as preexposure prophylaxis (PrEP) is safe and partially effective in reducing HIV acquisition among MSM when provided with regular monitoring of HIV status and ongoing risk-reduction and PrEP medication adherence counseling.