Family and twin studies have shown that genetic factors play an important role in the etiology of panic disorder. However, linkage and association studies using DNA markers have yielded inconclusive results. Increased serotonin neurotransmission may cause or be related to panic disorder. Assuming that genes regulating the serotonin system are involved in the pathogenesis of panic disorder, the authors searched for a genetic association of panic disorder with the serotonin 1A (HTR1A), 2A (HTR2A), and 2C (HTR2C) receptor genes. HTR1A, HTR2A and HTR2C polymorphisms were detected by the polymerase chain reaction method with analysis of restriction fragment-length polymorphisms (PCR-RFLP). The subjects were 63 biologically unrelated patients with panic disorder and 100 biologically unrelated normal control subjects who were native Japanese living in the western area of Japan. HTR1A and HTR2C showed no significant association with panic disorder. However, the frequency of the MspI A2 allele of HTR2A was significantly higher in the patients than in the normal control subjects. The study showed a positive association between panic disorder and the HTR2A gene, suggesting that HTR2A plays an important role in the pathogenesis of panic disorder.