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Objectives: The Salud Mesoamérica Initiative (SMI) is a three-operation strategy, and is a pioneer in the world of results-based aid (RBA) in terms of the success it has achieved in improving health system inputs following its initial operation. This success in meeting pre-defined targets is rare in the world of financial assistance for health. We investigated the influential aspects of SMI that could have contributed to its effectiveness in improving health systems, with the aim of providing international donors, bilateral organizations, philanthropies, and recipient countries with new perspectives that can help increase the effectiveness of future assistance for health, specifically in the arena of RBA. Methods: Qualitative methods based on the criteria of relevance and effectiveness proposed by the Development Assistance Committee of the Organization for Economic Co-operation and Development. Our methods included document review, key informant interviews, a focus group discussion, and a partnership analysis. Participants: A purposive sample of 113 key informants, comprising donors, representatives from the Inter-American Development Bank, ministries of health, technical assistance organizations, evaluation organizations, and health care providers. Results: During May-October 2016, we interviewed regarding the relevance and effectiveness of SMI. Themes emerged relative to the topics we investigated, and covered the design and the drivers of success of the initiative. The success is due to 1) the initiative's regional approach, which pressured recipient countries to compete toward meeting targets, 2) a robust and flexible design that incorporated the richness of input from stakeholders at all levels, 3) the design-embedded evaluation component that created a culture of accountability among recipient countries, and 4) the reflective knowledge environment that created a culture of evidence-based decision-making. Conclusions: A regional approach involving all appropriate stakeholders, and based on knowledge sharing and embedded evaluation can help ensure the effectiveness of future results-based aid programs for health in global settings. Inglés