Several lines of evidence suggest a contribution of adenosinergic neurotransmission to the development of panic disorder. We therefore hypothesized that variation in the A1 and A2a 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 A1AR and A2aAR 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 A1AR gene and two silent mutations (432C/T and 1083C/T) in the A2aAR 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 A2AR gene and panic disorder. Our findings thus lend further support to the hypothesis that the A2aAR 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.