Panic disorder (PD) is a complex and heterogeneous psychiatric condition. Dysfunction within the serotonergic system has been hypothesized to play an important role in PD. The novel brain-specific serotonin synthesizing enzyme, tryptophan hydroxylase 2 (TPH2), which represents the rate-limiting enzyme of serotonin production in the brain, may therefore be of particular importance in PD. We investigated the TPH2 703G/T SNP for association with PD. Patients with PD (n = 108), and control subjects (n = 247), were genotyped for rs4570625 (TPH2 703G/T). Male and female subjects were analyzed separately. The severity of their symptoms was measured using the Spielberger state-trait anxiety inventory (STAI), panic disorder severity scale (PDSS), anxiety sensitivity index (ASI), acute panic inventory (API), and Hamilton's rating scale for depression (HAMD). The genotype and allele frequencies of the PD patients and controls were analyzed using chi(2) statistics. There was a significant difference in the allele frequency in rs4570625 between the PD patients and normal controls. The T allele was significantly less frequent in the PD patients. We also found a significant association with rs4570625 in the female subgroup. There was no difference in symptom severity among the genotypes of this polymorphism. This result suggests that rs4570625 polymorphism may play a significant role in the pathogenesis of PD. Moreover, rs4570625 may have a gender-dependent effect on susceptibility to PD. Further studies are needed to replicate the association that we observed.