We sought to determine the real-world effectiveness of respiratory syncytial virus (RSV) immunoprophylaxis in a population-based cohort to inform policy. The study population included infants born 1996-2008 and enrolled in Kaiser Permanente Northern California. During the RSV season (November-March), RSV immunoprophylaxis administration and the following 30 days were defined as RSV immunoprophylaxis protected period(s), and all other days as unprotected period(s). Bronchiolitis hospitalizations were determined using the International Classification of Diseases Ninth Revision codes during RSV season. We used proportional hazard model to estimate bronchiolitis hospitalization risk comparing infants’ protected period(s) with unprotected period(s). Infants who ever received RSV immunoprophylaxis had a 32% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.68, 95% confidence interval: 0.46, 1.00) when comparing protected periods to unprotected periods. Infants with chronic lung disease (CLD) had a 52% decreased risk in bronchiolitis hospitalization (adjusted hazard ratio = 0.48, 95% confidence interval: 0.25, 0.94). Under the new 2014 American Academy of Pediatrics (AAP) guidelines, 48% of infants eligible based on in-place AAP guidelines at birth would no longer be eligible, but nearly all with CLD remain eligible. RSV immunoprophylaxis is effective in decreasing hospitalization. This association is greatest for infants with CLD, a group still recommended for receipt under the new AAP guidelines.