To evaluate risk factors for a first generalized tonic-clonic seizure (GTCS) in adults (=15 years), we performed a multicenter, case-control study involving eleven first-referral neurological departments in north-western Italy. The study enrolled 278 patients with a first GTCS, and 556 age- and sex-matched hospital controls. Cases and controls were interviewed through a questionnaire (inter-rater and index-proxy agreement varied between 75% and 100% for the different questions). Risk factors significantly associated with a first GTCS were: severe head trauma (odds ratio 9.9; 95% confidence limits 2.0-67.1), siblings with seizures (5.7; 1.7-21.4), alcohol intake >50 grams/day (4.9; 3.1-7.9), history of stroke (3.8; 1.8-8.0), complications of delivery (2.7; 1.5-5.1), other relatives with seizures (2.4; 1.3-4.6), sleep deprivation (2.4; 1.4-4.1), low gestational age (1.9; 1.1-3.4), mild-moderate head trauma (1.8; 1.2-3.0), and low birth weight (1.6; 1.0-2.7). Genetic and late acquired factors and life habits are major risk factors for a first GTCS in adults, while pre- and perinatal events play only a minor role.