OBJECTIVES: Respiratory syncytial virus (RSV) is a primary cause of lower respiratory tract infection in infants and children and leads to substantial morbidity. Palivizumab is a monoclonal antibody demonstrated to significantly reduce the frequency of hospitalizations for RSV infection in high-risk populations, including preterm infants and children with bronchopulmonary dysplasia and congenital heart disease. National costs of implementing a childhood prophylaxis program have not been well characterized.   The objective was to compare the financial impact of implementing a RSV prevention program in high-risk infants using palivizumab, to three established childhood prophylaxis programs in Mexico: 13-valent pneumococcal conjugate vaccine (PCV13); quadrivalent human papillomavirus (HPV) vaccine; and Bordetella pertussis (B. pertussis) vaccine.   METHODS: A model was developed to estimate the one-year budget impact of palivizumab for the prevention of severe RSV infection in high-risk populations in Mexico, from the national healthcare perspective. Model inputs were derived following a literature review on the healthcare system, and included the epidemiology of severe RSV infection in Mexico and Latin America, with appropriate Mexican resource utilization and cost estimates.   RESULTS: The cost of prophylaxis with palivizumab was approximately MXN$283 million. The corresponding costs for PCV13, HPV vaccine, and B. pertussis vaccine were estimated at MXN$1.1 billion; MXN$579 million; and MXN$636 million, respectively. Total disease cost estimates were MXN$878 million for RSV infection, MXN$123 million for pneumococcal diseases, MXN$199 million for HPV, and MXN$258 million for B. pertussis. Cost offsets in Year 1 after adoption of the immunization program totaled MXN$23 million for RSV infection, MXN$38 million for pneumococcal diseases, MXN$133 million for HPV, and MXN$206 million for B. pertussis.   CONCLUSIONS: This model suggests that targeting RSV prophylaxis to high-risk populations can lead to substantial cost offsets, which are consistent with or improve on the budget impact of other preventive health programs for childhood diseases in Mexico.