Trivalent inactivated influenza vaccine has been shown to reduce the number of influenza-related outpatient visits and hospitalizations of children up to 24 months of age. The American Academy of Pediatrics, Centers for Disease Control, and Advisory Committee on Immunization Practices recommend that the influenza vaccine be administered to the first-person contacts of infants less than 6 months of age. However, the economic implications of increasing immunization rates by using the neonatal intensive care unit (NICU) as an arena to capture the parents of these infants has not been fully evaluated. We sought to examine the direct and indirect costs of a program to administer the influenza vaccine to parents in the NICUs of a cohort of tertiary-care units primarily serving a low socioeconomic population. The probabilities of infants being hospitalized because of infection from contact and of the efficacy of prophylaxis used in the present study were based on published results where possible, with an estimated 10% reduction in hospitalization of patients whose parents had received the vaccine. Variables in the 3- and 4-tiered analyses included chronic lung disease status, estimation if patients had siblings, vaccination status of siblings, seroconversion rate of vaccine, and parental vaccination status. Two thousand six hundred and thirty-two patients were analyzed using 2003 admission data from the New York City Regional Perinatal Center, which encompasses 11 level III NICUs. Hospitalization costs, indirect costs, and outpatient costs were assessed using previously published standard calculations. On the basis of this computer model, costs were $188 per patient per influenza season, including $6.80 per patient in outpatient costs. Administration of an NICU-based influenza vaccine increased costs to $200 per patient per influenza season, but decreased outpatient costs to $1.40 per patient. For cost savings to equal costs of vaccine administration, there must be either a 20% reduction in influenza hospitalizations of NICU patients or an increase in the sample size per influenza season to 4000 patients. The cost of administration of the influenza vaccine to parents of NICU patients is higher than the financial burden of influenza in this population as long as the sibling immunization rate remains low. Cost savings do not occur until the treated cohort increases to 4000 patients or the incidence of lung disease in this population increases. Further studies are needed to validate the cost savings of this mode and more accurately assess the financial savings.