Cytomegalovirus (CMV) infection is the leading cause of congenital cognitive deficit, visual impairment and hearing loss in the US. Clinical trials are underway to evaluate the efficacy of CMV vaccine candidates in seronegative females. The optimal age of such vaccination depends on the interplay among age-specific transmission dynamics, vaccine efficacy and vaccine waning. We developed an age-structured model of CMV transmission dynamics in the US and estimated age-specific transmission rates of CMV based on age-stratified CMV prevalence, congenital infections per birth, breastfeeding patterns and demographic data. We found that the optimal age of vaccination depended on the duration of vaccine protection. For most scenarios, the optimal age of vaccination was between 19 and 21 years of age. However, for a rapidly waning vaccine, the optimal age of vaccination can shift to infants under 1 year. This shift arises when the duration of vaccine efficacy is too brief to offer appreciable protection during the child-bearing years. In this case, it becomes more effective to achieve indirect protection by reducing transmission from infants, the transmissibility from whom was estimated to be an order of magnitude higher than other age classes. Knowledge of vaccine waning is paramount to optimizing CMV vaccination and is thus a key parameter for longitudinal clinical evaluation.