The purpose of this guidance is to provide to sponsors nonclinical and clinical recommendations specific to the development of systemic drug products, with a focus on long-acting systemic drug products, regulated within the Center for Drug Evaluation and Research at the Food and Drug Administration (FDA) for the prevention of sexually acquired human immunodeficiency virus-1 (HIV-1) infection. Specifically, this guidance addresses the FDA’s current thinking regarding the overall development program and clinical trial designs to support the development of systemic drug products for the prevention of HIV-1 infection. Investigational drug products for further development as pre-exposure prophylaxis (PrEP) can include the following: (1) an oral drug product approved for the treatment of HIV-1 infection that is subsequently developed as oral PrEP; (2) an oral drug product approved for the treatment of HIV-1 infection that is reformulated as a long-acting drug product or other delivery system for PrEP; or (3) a new investigational drug product.