BACKGROUND AND PURPOSE: Perinatal arterial ischemic stroke (PAIS) is a common cause of hemiplegic cerebral palsy in children. The diagnosis of PAIS is based on cerebral imaging. The objective of our study was to determine prenatal risk factors associated with PAIS. METHODS: A retrospective case-control study was nested in the whole population of Burgundy, France, from January 2000 to December 2007. Case patients were confirmed by review of brain imaging and medical records. Three control subjects per case were randomly selected from the study population by sex, term, place, and year of birth. RESULTS: PAIS was confirmed in 32 patients and its incidence was one per 4400 live births. In comparison to control subjects, clinical conditions significantly associated to cases were gestational diabetes (16.1% versus 4.2%; P=0.04), fetal heart rate abnormalities (35.5% versus 10.9%; P=0.001), and meconium-stained liquor (40% versus 12%; P\textless0.001). At the limit of statistical significance were found maternal smoking before (39.3% versus 22.9%; P=0.08) and during pregnancy (32.1% versus 16.7%; P=0.07), cord abnormalities (29% versus 14.1%; P=0.06), and cesarean delivery (28.1% versus 14.6%; P=0.08). In the multivariate analysis, maternal smoking during pregnancy (OR, 3.1; 95% CI, 1.1-8.8; P=0.04) was the only risk factor significantly associated with PAIS. CONCLUSIONS: This study is the first to identify maternal smoking during pregnancy as an independent prenatal risk factor of PAIS. Additional prospective studies are needed to confirm this result and to investigate the role of maternal smoking in fetal and neonatal thrombogenesis.