OBJECTIVES: Palivizumab prophylaxis against respiratory syncytial virus (RSV) is provided monthly during the RSV season. CARESS is a prospective registry of infants who received ≥1 dose of palivizumab across 32 Canadian sites during 7 seasons. The objective is to determine factors associated with palivizumab compliance. METHODS: Neonatal and demographic data were collected at enrolment. Palivizumab utilization, compliance, and outcomes related to respiratory illness (RI) and RSV hospitalization were collected monthly. Compliance was defined as receipt of all expected injections at 25–35 day intervals during the RSV season. RESULTS: 13,310 infants were enrolled. Infants received 89.0% ± 18.23% of their expected injections and 9745 (73.2%) were administered within appropriate inter-dose intervals.Compliant versus non-compliant infants had a rate of 9.2 RSV and 57.5 RI versus 11.7 RSV and 65.5 RI hospitalizations / 100-patient-years respectively. Compliance differed between prophylaxis indications (χ2=24.6, p<0.0005); with congenital heart disease the most non-compliant (CHD; n=668, 47.2%), followed by chronic lung disease (CLD; n=470, 44.8%), prematurity (≤35 weeks gestational age; n=3643, 41.6%) and other medical disorders (n=831, 39.6%). A greater proportion of non-compliant infants were Aboriginal (4.8% vs. 2.4%, χ2=57.8, p<0.0005), attended daycare (4.0% vs. 3.3%, χ2=5.0, p=0.03), had a mother who smoked (17.1% vs. 12.0%, χ2=69.0, p<0.0005), and lived with ≥1 smoker (31.7% vs.26.1%, χ2=49.7, p<0.0005). Significant factors independently associated with compliance (OR, 95%CI) were: maternal education (1.38, 1.22–1.58), Aboriginal descent (0.57, 0.47–0.70), smoke exposure (0.70, 0.52–0.94), CLD (0.74, 0.56–0.99), maternal smoking (0.79, 0.68–1.01), daycare (0.82, 0.68–0.99), and indication for prophylaxis. Compliance by both expected number of injections and inter-dose intervals was associated with lower hazard rates of RI hospitalization (HR=0.86, 95%CI=0.74-0.99, p=0.04). CONCLUSIONS: Higher maternal education and lower RI hospitalization was associated with full compliance where as non-compliance was associated with other demographic factors and differed by palivizumab indication.