Family, twin, and segregation analytic studies indicate a complex genetic contribution to panic disorder with an estimated heritability of 48%. Angiotensin-converting enzyme (ACE) degrades substance P, which has been implicated in anxiety-related behaviour. ACE has been suggested as a potential risk factor in the pathogenesis of panic attacks. A functional insertion deletion (I/D) polymorphism in the ACE gene was suggested to be associated with panic disorder in a potentially gender-specific way ( Olsson et al. 2004 ). The present study aimed to replicate this finding and thereby to further elucidate the role of ACE gene variation in the pathomechanism of panic disorder. The ACE I/D polymorphism was genotyped in a sample of 102 German patients with panic disorder with or without agoraphobia as well as a healthy German control group matched with regard to age and sex (n = 102). In the male subgroup (n = 43) of panic patients a significant association of the ACE I allele (P = 0.0474) and genotypes containing the I allele (P = 0.0195), respectively, was observed. The present results provide further support for a potentially male-specific role of the less active ACE I allele in the pathogenesis of panic disorder, possibly by altering substance P levels.