This meta-analysis synthesized 37 HIV prevention interventions (from 28 studies) that were evaluated in Latin American and Caribbean nations. These studies were obtained through systematic searches of English, Spanish, and Portuguese-language databases available as of January 2009. Overall, interventions significantly increased knowledge (d = 0.40) and condom use (d = 0.25) but the effects varied widely. Interventions produced more condom use when they focused on high-risk individuals, distributed condoms, and explicitly addressed social-cultural components. The best-fitting models utilized factors related to geography, especially indices of a nations' human development index (HDI) and income inequality (i.e., Gini index). Interventions that provided at least 3 h of content succeeded better when HDI and income inequality were lower, suggesting that intensive HIV prevention activities succeed best where the need is greatest. Implications for HIV intervention development in Latin America and the Caribbean are discussed.