The transcription factor activator protein 2 (AP-2) gene is a possible candidate gene for schizophrenia, since it maps near D6S470, a marker on chromosome 6p24 that provided evidence of linkage to schizophrenia. In the present study we analyzed the promoter region and the whole coding region of the human AP-2 gene in order to identify genetic variations that may lead to the modification of AP-2 expression or the alteration of protein function, contributing to schizophrenia or particular schizophrenic phenotypes. Genomic DNA was isolated from the whole blood samples of 87 unrelated schizophrenics and 100 healthy controls. Polymerase chain reaction (PCR) was performed, using 15 primer sets that spanned the promoter region and the whole coding region, and amplified products were screened by single-strand conformational polymorphism (SSCP) analysis. Aberrant SSCP patterns were analyzed by direct sequencing. Three novel polymorphisms were found in the promoter region; two relatively common (-90G-->C, -803G-->T) and one rare (-1769G-->A). Polymorphic status at both loci suggested strong linkage disequilibrium between the -90G and -803G alleles, and between the -90C and -803T alleles. Although no significant differences in genotypic and allelic frequencies at the -90 and -803 loci were found between patients and controls, significant differences in the distribution of genotypes at the -90 (P = 0.008) and -803 (P = 0.037) loci were observed in patients with an episodic course compared with controls. However, the difference for the -803 locus was not significant after Bonferroni correction for multiple comparisons. Our data provided no direct evidence of an association between schizophrenia and the polymorphisms of the AP-2 gene, although the positive result at the -90 locus in schizophrenics with an episodic course is potentially interesting.