L1CAM, a neural cell adhesion molecule, plays an important role in the development of the central nervous system. The human L1CAM gene is located in Xq28. Mutations in the gene are responsible for a wide spectrum of neurological abnormalities and mental retardation. Schizophrenia may result from early neurodevelopmental abnormalities. We screened 30 male and 30 female schizophrenic patients for their genomic sequence of the L1CAM gene in order to determine the DNA sequence variations. Three novel variations located in exon 18 (10564 G > A, GG/AA at codon 758), intron 11 (8575 A > C), and intron 25 (13504 C > T) were detected. An association study of the identified polymorphisms was then performed in a Japanese sample of 152 male and 115 female patients with schizophrenia and 121 male and 114 female control subjects. A statistically significant increase in the count of the 13504 T-allele was observed in the male patients, compared to the male controls, with no differences in the variations of exon 18 or intron 11. There was no statistically significant change in the distribution of allele or genotype of any variations in the female schizophrenics, in comparison with the female controls. These results suggest that the polymorphism in intron 25 plays a role in the genetic predisposition of male schizophrenia in the Japanese sample. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 105:99–104, 2001. © 2001 Wiley-Liss, Inc.