New vaccines have been demonstrated to be effective in reducing morbidity and mortality, particularly in children, but come at increased costs to societies, governments, and their national immunization programs compared with other traditional childhood vaccines. Rational allocation of available resources requires systematic collection of the evidence base to decide whether to introduce a new vaccine, an important component of which is cost-effectiveness analysis. In this article, we develop in-depth case studies to examine the country experience of conducting cost-effectiveness analysis with the support of Pan American Health Organization ProVac Initiative and the implications of its process for decision making on new vaccine introduction in Latin America and the Caribbean. Key lessons regarding how cost-effectiveness analysis may be effectively used to inform evidence-based immunization policy are highlighted, drawing from the experience of Nicaragua and Paraguay. Based on the lessons identified, the vision going forward will focus on promoting the sustainability of multidisciplinary country teams while continuing to prioritize capacity development as an overarching guiding principle for preparing countries to face future new vaccine policy decisions. © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR).