Immunoprophylaxis is the only pharmaceutical intervention for mitigating respiratory syncytial virus (RSV) infection. Patient level data on adherence to American Academy of Pediatrics (AAP) immunoprophylaxis recommendations are limited. This study characterizes adherence to AAP guidelines in privately insured and Medicaid populations. We performed a retrospective birth cohort study of 211 174 privately insured children in Northern California; and 458 837 publicly insured children in Tennessee born between January 1, 1996 and December 31, 2008. Adherence to the AAP guideline was defined for eligible infants as the number of doses of RSV immunoprophylaxis administered over the number recommended for 4 mutually exclusive eligibility groups: chronic lung disease, prematurity <29 weeks, prematurity <32 weeks, and other eligibility. We identified 3456 California (Kaiser Permanente Northern California [KPNC]) and 12 251 Tennessee (Tennessee Medicaid [TennCare]) infants meeting AAP eligibility criteria. Immunoprophylaxis administration increased over the study period, from 15% for all eligible groups in 1998 to 54% in 2007. Adherence was highest among babies with chronic lung disease (KPNC 67% and TennCare 55%). Nonadherence (0% adherence) was greatest among infants of African American mothers (adjusted odds ratio [AOR] = 1.32; 95% confidence interval [CI] = .98-1.78); those with mothers with less than a high school education (AOR = 1.58; CI = 1.09-2.30) in KPNC; and in infants of Hispanic mothers in TennCare (AOR = 1.65; CI = 1.24-2.20). In KPNC, 0.11% of ineligible term infants and 5% of ineligible premature infants received immunoprophylaxis; the corresponding proportions in TennCare were 1% and 11%. Overall adherence with AAP guidelines has increased over time. Considerable overuse and underuse of immunoprophylaxis are evident with identifiable risk groups to target for improvement.