OBJECTIVES: Palivizumab given monthly prior to and throughout the RSV season reduces incidence of RSV hospitalization (RSV-H) in premature infants, infants with chronic lung disease of prematurity (CLDP), and children with hemodynamically significant congenital heart disease (CHD). This study determines the impact of non-compliance with palivizumab dosing and risk of RSV-H among Medicaid-insured infants. METHODS: Infants with prematurity [≤34 weeks' gestational age (wGA)], CLDP and/or CHD born and discharged between May 1 and September 30 who received ≥1 dose of palivizumab during their first RSV season (October 1 - April 30) were identified retrospectively in Medicaid claims data from 12 states. Palivizumab compliance (first dose by November 30, ≥5 consecutive doses during the RSV season, and no gaps >35 days between consecutive doses) was evaluated across 6 seasons (2003-2009). The percentage of infants with in-season RSV-H was calculated for non-compliant and compliant cohorts. Logistic regression of RSV-H was performed, adjusting for non-compliance, wGA, birthweight, comorbidities, and other demographic/clinical characteristics. RESULTS: A total of 8443 high-risk infants received ≥1 dose of palivizumab. Approximately 67% of all infants were non-compliant. The percentage of infants with RSV-H was significantly higher among non-compliant vs. compliant infants (12.0% vs. 7.4%, P<0.001). In the logistic regression model, non-compliant compared to compliant infants had a 1.31 (95% CI= 1.18, 1.46) increased odds of RSV-H, and odds were also higher for males, rural residents, capitated healthplan members, infants who required neonatal intensive care at birth, gestational age <32 weeks or unknown (vs. 33-34 weeks), age >3 months at season onset, and comorbidities (including CLDP/CHD) or emergency room/hospitalization prior to first dose (all P≤0.001). CONCLUSIONS: Non-compliance with palivizumab was common and significantly increased the risk of RSV-H in this Medicaid population. Intervention strategies are needed to improve palivizumab administration among Medicaid infants prior to and throughout the RSV season.