Using a pharmacogenetic approach in 185 schizophrenics who have been prospectively assessed for clozapine response, we have examined the hypothesis that polymorphisms in the 5-HT2A (HTR2A), and 5-HT2C (HTR2C) genes are involved in its variable response. A-1438 A-->G polymorphism in the putative promoter and a silent T-->C 102 substitution in HTR2A were in almost complete linkage disequilibrium, and neither was associated with response (T-->C. 102 allele: chi 2 = 0.02; 1 df, p = .90; genotype: chi 2 = 0.02, 2 df, p = .99). A his452tyr HTR2A polymorphism was found to be associated with clozapine response (his452tyr allele: chi 2 = 6.43, 1 df, p = .01 [p = .04, Bonferroni corrected]; genotype: chi 2 = 6.54, 2 df, p = .04 [p = .16, Bonferroni corrected]). No HTR2A haplotype was associated with response. Interethnic differences were observed in the frequencies of the cys23ser HTR2C polymorphism. This polymorphism was not significantly associated with response in either of the ethnic groups (Caucasian and African American genotype: chi 2 = 3.46, 2 df, p = .18; chi 2 = .31, 2 df, p = .86, respectively). Although replication is required, the overall results suggest that the his452tyr HTR2A polymorphism may be involved in clozapine response.