This study investigates program-related investments (PRIs), which are mechanisms that foundations can use to achieve charitable purposes while generating moderate financial returns. There is a growing interest in PRIs and other similar market-based approaches among practitioners of philanthropy recently. We examine the internal and external factors that influence PRIs by U.S. foundations through both quantitative and qualitative analyses. By analyzing the Internal Revenue Service (IRS) and Foundation Center data, we find that foundations with more financial and human resources are more likely to adopt PRIs initially and also more intensively engage in PRIs. Foundations of 25 years or older invest less money in PRIs than younger foundations. Findings from the interviews with eight foundations reveal additional factors influencing foundations’ PRI activities, including staffing and expertise, the board and executive leadership, changes in the legal and economic environment, sectoral trends and peer networks, and the interests and needs of PRI recipients.