Because disorders of neuronal migration to cerebral cortex in humans are believed to occur in the first half of gestation, prenatal events or genetic factors are suspected to have a pathogenetic role. We evaluated this by comparing the frequency of potentially harmful prenatal events and of genetic factors in a series of 40 patients (38 with epilepsy) with neuronal migration disorders (NMD) and in 40 epileptic controls, using a predetermined standardized questionnaire to minimize interviewer bias. Potentially harmful prenatal events (significant maternal physical trauma, ingestion of medications, exposure to roentgenograms, infections, uterine or metabolic abnormalities) were reported in the pregnancy histories of 58% of patients with NMD but in only 15% of epileptic controls (p = 0.0002). In contrast, peri- and postnatal potentially relevant etiologic factors were reported in the histories of only 22% of patients with NMD but in 50% of the epileptic controls (p = 0.01). Genetic factors (a family history of epilepsy, mental retardation, or congenital malformations of the CNS) were noted in 13 and 20% of the families, respectively. Stillbirths occurred only in the group with NMD, accounting for 3.06% of sibling pregnancies. The findings suggest that prenatal potentially harmful environmental events play a central role in the pathogenesis of NMD in humans.