To make appropriate use of the growing economic evidence base in health care, developing countries need applications relevant to their own national health objectives. One objective is protection for individuals and governments against the financial risks of ill health, more critical in low-resource settings. Yet, advancements in cost-effectiveness analysis (CEA) have not focused on the importance of efficiency in contributing to this goal. The lowest income nations also rely heavily on external funds from donor countries and organizations. While the recent emergence of non-traditional donors has greatly increased funding levels for global health, the large scale, narrow focus and time limitations of some of the funding have also raised questions of their effects on national health priorities as well as on the opportunity costs of the interventions supported by this funding. In attaining efficiency with a view towards minimizing financial risk, CEA must address two issues in this case: that the additional resources are efficiently allocated and that the resources themselves are not a source of financial risk. This doctoral project proposes a conceptual framework for a CEA “reference case” in the broader context of health financing in developing countries. Suggested modifications of the prevailing reference cases are literature-based, iteratively guided by key informants. Costing and sensitivity analysis with respect to external funding are highlighted. An application to the introduction of rotavirus immunization illustrates the framework. The conceptual framework anticipates the imminent introduction of expensive new vaccines targeted at resource-poor, donor-dependant health systems. It allows analysts and policy-makers to harmonize efficiency and financial risk objectives. It also helps donors in assessing aid effectiveness of assisted programs. Ultimately, this framework improves the transferability and generalizability of existing CEA results by suggesting adjustments relevant to developing countries.