Tardive dyskinesia (TD) is a common and potentially irreversible side effect associated with long-term treatment with typical antipsychotics. Approximately, 80% or more of patients with schizophrenia are smokers. Smoking is a potent inducer of the CYP1A2 enzyme, and is known to cause a significant decrease in plasma concentrations of some antipsychotics. Therefore, person-to-person differences in the extent of CYP1A2 induction by smoking may contribute to risk for the development of TD. Recently, a (C-->A) genetic polymorphism in the first intron of the CYP1A2 gene was found to be associated with variation in CYP1A2 inducibility in healthy volunteer smokers. The aim of this study was to test the clinical importance of the (C-->A) polymorphism in CYP1A2 in relation to TD severity. A total of 85 patients with schizophrenia were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS), and were subsequently genotyped for the (C-->A) polymorphism in CYP1A2. The mean AIMS score in patients with the (C/C) genotype (associated with reduced CYP1A2 inducibility) was 2.7- and 3.4-fold greater than in those with the (A/C) or (A/A) genotype, respectively (F[2,82] = 7.4, P = 0.0007). Further, a subanalysis in the 44 known smokers in our sample, revealed a more pronounced effect. The means AIMS score in smokers was 5.4- and 4. 7-fold greater in (C/C) homozygotes when compared to heterozygotes and (A/A) homozygotes, respectively (F[2,41] = 3.7, P = 0.008). These data suggest that the (C-->A) genetic polymorphism in the CYP1A2 gene may serve as a genetic risk factor for the development of TD in patients with schizophrenia. Further studies in independent samples are warranted to evaluate the applicability of our findings to the general patient population receiving antipsychotic medications.