Several studies showed the density of D2 receptors was elevated in postmortem brains from schizophrenics. Genes which operate at the level of gene activation may be associated with the pathogenesis of schizophrenia. Arinami et al. [(1997) Human Molecular Genetics 6, 577-582] found a polymorphism in the 5'-flanking region of the D2 receptor gene designated as -141C Ins/Del. The promoter activity by luciferase assay of a plasmid containing the -141C Ins allele was higher than in the one containing the -141C Del allele. In addition, the -141C Ins allele frequency was significantly higher in schizophrenics than in control subjects. We replicated the -141C Ins/Del polymorphism in 170 schizophrenics and 121 healthy control subjects. The number of schizophrenics with the -141C Ins/Ins genotype was significantly higher than that of control subjects (P = 0.038). The frequency of the -141C Ins allele was significantly increased in the schizophrenics compared with the control subjects (P = 0.042). The mean age of onset for the patients with -141C Ins/Del was significantly lower than that for the patients with -141C Ins/Ins (P = 0.029). There was no association between the genotype and either positive symptoms or the response to antipsychotic medication. Our results suggest that the -141C Ins/Del polymorphism may affect the susceptibility to schizophrenia.