Proinflammatory cytokines, including interleukin (IL)-1, are known to modulate effects of neurotoxic neurotransmitters discharged during excitation or inflammation in the central nervous system (CNS). They also regulate development of glial scars at sites of CNS injury. To elucidate a genetic predisposition of temporal lobe epilepsy with hippocampal sclerosis (TLE-HS ؉ ), we studied polymorphisms in the IL-1, IL-1␣, and IL-1 receptor antagonist (IL-1RA) genes in 50 patients with TLE-HS ؉ and in 112 controls. Fifty-three patients who had TLE without HS were also examined (TLE-HS ؊ ) as disease controls. The distribution of the biallelic polymorphism in the promoter region at position ؊511 of the IL-1 gene (IL-1B؊511) was significantly different both between TLE-HS ؉ patients and controls and between TLE-HS ؉ and TLE-HS ؊ patients. The differences were due to overrepresentation of the homozygotes for IL-1B؊511,2ء which is suggested to be a high producer of IL-1, in TLE-HS ؉ patients compared with both controls and TLE-HS ؊ patients. In contrast, there was no difference between TLE-HS ؊ patients and controls. Our data suggest that, in the homozygotes for IL-1B؊511,2ء minor events in development such as febrile convulsions could set up a cascade leading to HS.