A large number of studies have reported an association between epilepsy and major psychiatric conditions. This study investigated the association between epilepsy and later schizophrenia, utilizing a historical-prospective, population-based design. Of the 861,062 17-year-old male adolescents consecutively screened by the Israeli Draft Board and found free of major mental illness, 0.06% suffered from severe, treatment-refractory epilepsy, 0.25% had treated, controlled epilepsy, and 0.16% had a history of seizures which had abated 5 or more years prior to screening. Hospitalization for schizophrenia was ascertained through the Israeli National Psychiatric Hospitalization Case Registry, with an average follow-up of 9.6±1.0years (range: 1.0-10.0years). Risk of hospitalization was calculated using Cox regression analyses, compared to socioeconomic-adjusted risk of hospitalization in the general population of male adolescents. Among adolescents whose epilepsy was nonresponsive to medication, the adjusted risk of hospitalization was significantly increased for schizophrenia (HR=3.89, 95% CI=1.75-89.67). Male adolescents with successfully treated epilepsy were not at increased risk for schizophrenia. Male adolescents with severe, treatment-refractory epilepsy are at increased risk of later schizophrenia. Future studies attempting to understand the biology of this association might focus on this subset of patients, and these patients should be monitored for the appearance of psychosis.