Background The serotonin transporter (5-HTT) and tryptophan hydroxylase (TPH) gene are important candidate genes for the psychiatric disorders. Many studies of patients with anxiety disorders have found abnormalities of serotonin metabolism and dysfunction of regulation in the transporter itself. In this study, we hypothesize that genetic variation in the 5-HTT and TPH gene may have an effect on the etiology of generalized anxiety disorder (GAD). Methods Using a polymerase chain reaction-based technique, the allele and genotype frequencies of three polymorphisms in the serotonin transporter gene (a deletion/insertion polymorphism in the transcriptional control region and a variable number of tandem repeats in intron 2) and TPH gene (A218C in intron 7) were analyzed in 138 patients with GAD and 90 healthy controls. These two groups were matched for ethnic and geographic origin. Results The frequencies of 5-HTT gene-linked functional polymorphic region (5-HTTLPR) SS (short/short) genotype were significantly higher in GAD patients than in control 2 subjects (68% versus 49%, x(2) = 12.274, df = 2, P = 0.002), and the frequencies of S (short) allele observed in the GAD patients were higher than those in healthy subjects (79 versus 71%, x(2) = 4.063, df = 1, P = 0.044). The odds ratio for the SS genotype versus the other two genotypes was 2.33 (95% confidence interval, 1.29-3.86). Similarly, the odds ratio for the S allele versus L allele was 1.56 (95% confidence interval, 1.01-2.41). The genotypic and allelic distribution of 5-HTT VNTR and TPH A218C polymorphisms did not show statistically significant differences between patients and controls. Conclusion Our findings support that the presence of 5-HTTLPR-SS genotype may increase the risk of GAD. (c) 2005 Lippincott Williams & Wilkins.