Several lines of evidence suggest a contribution of adenosinergic neurotransmission to the development of panic disorder. We therefore hypothesized that variation in the A 1 and A 2a adenosine receptor (AR) genes modifies genetic susceptibility to panic disorder. To test this hypothesis, we screened 38 patients with panic disorder for mutations in the coding sequence of the A 1 AR and A 2a AR genes. An association study between the identified DNA sequence variants and panic disorder was performed in an extended sample of 89 patients and matched controls. One silent mutation (716T/G) in the A 1 AR gene and two silent mutations (432C/T and 1083C/T) in the A 2a AR gene were detected. The association sample shows a significant association between the 1083T allele (P= 0.01) and 1083T/T genotype (P= 0.024) of the A 2A R gene and panic disorder. Our findings thus lend further support to the hypothesis that the A 2a AR gene, or a locus in linkage disequilibrium with it, confers susceptibility to panic disorder. Replication studies in independent samples with nuclear families applying the transmission disequilibrium test (TDT) are warranted.