Background: The cost-effectiveness of palivizumab is subject of vigorous debate. It is recognized that a policy of using palivizumab for all children who meet the licensed indication is not cost-effective, but most clinicians feel that its use is justified in certain subgroups. Objective: To systematically review the literature on the cost-effectiveness of palivizumab prophylaxis in the following subgroups: 1) preterm infants born before 32 weeks gestational age (WGA), 2) preterm infants born between 32 and 35 WGA, 3) children with chronic lung disease, and 4) children with congenital heart disease. Methods: We searched Pubmed, EMBASE and the latest versions of the DARE, NHS EED and HTA databases from inception to February 2010 using the terms cost, cost-effectiveness, respiratory syncytial virus and palivizumab. Results: Seventeen studies evaluating the cost-effectiveness of palivizumab were included. The cost-effectiveness of palivizumab for the subgroups of children born before 32 WGA, children born between 32 and 35 WGA, children with chronic lung disease (CLD), and children with congenital heart disease was studied in 8, 9, 8, and 6 studies, respectively. The incremental cost-effectiveness ratios varied considerably both within and between subgroups. Sensitivity analyses showed that cost-effectiveness was mainly driven by the mortality rate due to RSV infection. Differences in hospitalization rates, industry sponsoring and study year were also associated with differences in cost-effectiveness, but these differences could be attributed to differences in mortality rates. Conclusion: The cost-effectiveness of prophylactic treatment of RSV infection with palivizumab in subgroups varies considerably, and is certainly not always below the threshold. The cost-effectiveness is mainly sensitive to mortality rates of RSV infection. This systematic review indicates that future research should focus on the major uncertainties in costeffectiveness, particularly RSV-related mortality rate.