Abstract Experimental studies on serotonin (5-HT) availability suggest a role for 5-HT synthesis rate in panicogenesis. Recently, it has been discovered that the tryptophan hydroxylase gene isoform 2 (TPH2), rather than TPH1, is preferentially expressed in the neuronal tissue and, therefore, is primarily responsible for the regulation of brain 5-HT synthesis. In the present case–control genetic association study we investigated whether panic disorder (PD) phenotypes are related to two single nucleotide polymorphisms (SNP) of TPH2, rs1386494 A/G and rs1386483 C/T. The study sample consisted of 213 (163 females and 50 males) PD patients with or without affective comorbidity and 303 (212 females and 91 males) matched healthy control subjects. The allelic and genotypic analyses in the total sample did not demonstrate significant association of PD with the studied SNPs, suggesting that these polymorphisms may not play a robust role in predisposition to PD. However, an association with rs1386494 SNP was observed in the subgroup of female patients with pure PD phenotype, indicating a possible gender-specific effect of TPH2 gene variants in PD.