Palivizumab prophylaxis has been demonstrated to reduce the number of hospitalizations attributable to respiratory syncytial virus in high-risk infants. However, as palivizumab acquisition costs are high, quantifying cost-effectiveness is important. The primary aim of this review was to examine the cost-effectiveness of palivizumab across numerous indications in high-risk infants and to report on factors that may impact outcomes. A systematic literature search was conducted to identify pharmacoeconomic analyzes of palivizumab compared to no prophylaxis for respiratory syncytial virus in infants and young children. A total of 28 articles met inclusion criteria and were subsequently assigned quality scores according to the Quality of Health Economic Studies criteria. Results varied according to perspective, input parameters, outcome measures, populations and base-case and sensitivity analyses. Overall, cost-effectiveness results were inconsistent. Some studies reported favorable outcomes, while others did not, or were inconclusive. Factors to consider in the interpretation of such economic evaluations are discussed.