A population-based study of the impact of palivizumab on confirmed Respiratory Syncytial Virus (RSV) hospitalizations over a 7-year period within and between two similar health regions . Clinicians in Calgary implemented palivizumab prophylaxis for high-risk infants during the last four RSV seasons; clinicians in Edmonton did not. The two cities are part of a unified health care system and similar sociodemographics. Infants <36 weeks (wk) of gestational age (GA) were identified. RSV prophylaxis data and RSV-hospitalizations for high-risk infants eligible for prophylaxis were reviewed, as well as that of moderate-risk infants (33-35 weeks GA) for whom RSV prophylaxis was not given a high priority in the recommendations published by the Canadian Paediatric Society (CPS). Prevalence of RSV hospitalization before and after palivizumab was determined (1995-1998 and 1999-2002, respectively). There were 411 high-risk infants eligible for palivizumab prior to its provision (Pre) and 496 during the prophylaxis program (Post) in Calgary. There were 401 Pre and 425 Post in Edmonton, where no such prophylaxis program was implemented. In Calgary where palivizumab was offered (Post), RSV hospitalization was significantly reduced: 7.3% Pre versus 3.0% Post (OR, 2.53, 95% CI, 1.34, 4.76). No reduction was observed in Edmonton where palivizumab was not offered: 5.0% Pre versus 7.1% Post (OR, 1.45, 95% CI, 0.81, 2.59; P = 0.212). RSV hospitalizations did not change for moderate-risk infants not receiving palivizumab in Calgary (OR, 1.26, 95% CI, 0.75, 2.12; P = 0.389). An RSV prevention program with palivizumab for high-risk infants reduced RSV hospitalizations, providing "real life" evidence of the benefits of this prophylaxis strategy. Further research is required to determine if specific sub-sets of moderate-risk infants would also benefit from an RSV prophylaxis program with palivizumab.