Background: Acute minor infection was associated with childhood arterial ischemic stroke (AIS) in a retrospective study. In a prospective study, we tested the hypothesis that acute infection increases stroke risk, while vaccination against infection is protective. Methods: VIPS is an international multi-center prospective case-control study with a target enrollment of 350 cases of AIS (28 days-18 years old); parental interviews were conducted within 3 weeks of stroke occurrence in cases. Unmatched controls were identified and interviewed within 3 weeks of routine clinic visits for annual check-ups, migraine, or developmental delay, or urgent visits for trauma. Data were collected on recent infections and routine childhood vaccines. We explored attitudes toward vaccination by asking if the child had received all, most, some, few, or none of the routine vaccines expected for his/her age. Results: Data were available for 310 cases and 289 controls. Median (IQR) age was 7.5 (2.8, 14.2) and 8.2 (3.3, 12.8) years respectively (p=0.96). Infection ≤1week prior to stroke/interview date conferred a 6.5-fold risk of AIS (p<0.0001); the most common type of infection reported in this time period was upper respiratory (75% of controls and 50% of cases). In general, cases were under-vaccinated compared to controls (Table). Children reported to have had some/few/no routine vaccinations were at higher risk of AIS than those receiving all or most (OR 6.72, 95% CI 2.30, 19.6, p<0.0001). In logistic regression adjusted for age, ever having received an MMR, polio, or pneumococcus vaccine were each significantly protective against stroke. Conclusions: Recent infection confers an increased risk of childhood AIS, while routine vaccinations appear protective. This finding has positive implications for both primary and secondary stroke prevention.