Context Perinatal arterial ischemic stroke (PAS) is a common cause of hemiplegic cerebral palsy. Risk factors for this condition have not been clearly defined. Objective To determine maternal and infant characteristics associated with PAS. Design, Setting, and Patients Case-control study nested within the cohort of all 199176 infants born from 1997 through 2002 in the Kaiser Permanente Medical Care Program, a managed care organization providing care for more than 3 million residents of northern California. Case patients were confirmed by review of brain imaging and medical records (n=40). Three controls per case were randomly selected from the study population. Main Outcome Measure Association of maternal and infant complications with risk of PAS. Results The population prevalence of PAS was 20 per 100000 live births. The majority (85%) of infants with PAS were delivered at term. The following prepartum and intrapartum factors were more common among case than control infants: primiparity (73% vs 44%, P=.002), fetal heart rate abnormality (46% vs 14%, P<.001), emergency cesarean delivery (35% vs 13%, P=.002), chorioamnionitis (27% vs 11%, P=.03), prolonged rupture of membranes (26% vs 7%, P=.002), prolonged second stage of labor (25% vs 4%, P<.001), vacuum extraction (24% vs 11%, P=.04), cord abnormality (22% vs 6%, P=.01), preeclampsia (19% vs 5%, P=.01), and oligohydramnios (14% vs 3%, P=.01). Risk factors independently associated with PAS on multivariate analysis were history of infertility (odds ratio [OR], 7.5; 95% confidence interval [CI], 1.3-45.0), preeclampsia (OR, 5.3; 95% Cl, 1.3-22.0), prolonged rupture of membranes (OR, 3.8; 95% Cl, 1.1-12.8), and chorioamnionitis (OR, 3.4; 95% Cl, 1.1-10.5). The rate of PAS increased dramatically when multiple risk factors were present. Conclusions Perinatal arterial ischemic stroke in infants is associated with several independent maternal risk factors. How these complications, along with their potential effects on the placenta and fetus, may play a role in causing perinatal stroke deserves further study.