Despite incessant tachycardia, not all patients develop tachycardia-mediated cardiomyopathy. The cardiac renin-angiotensin system may be involved in cardiac remodelling and fibrosis. The level of angiotension-converting enzyme (ACE) in the serum is associated with a 287 bp insertion (I)/deletion (D) polymorphism in intron 16 of the ACE gene. The DD genotype is associated with increased serum ACE levels and a higher incidence of idiopathic dilated and ischemic cardiomyopathy. The objective of this study was to assess whether the ACE gene I/D polymorphism is responsible for development of tachycardia-mediated cardiomyopathy. We identified 20 consecutive patients with persistent tachycardia and cardiomyopathy who showed significant improvement in ejection fraction after rate control (group A, tachycardia cardiomyopathy group). We compared the I/D genotype frequency of group A with the gene frequency of a separate group of 20 patents who, despite rapid atrial arrhythmias had preserved left ventricular ejection fraction (group B, tachycardia without cardiomyopathy group). These two groups were then compared with 24 healthy normal volunteers (group C). After a mean follow-up of 30 months, group A patients showed improvement in ejection fraction from 20+/-7 to 43+/-9% (p<0.001). Group A had a significantly higher frequency of the DD genotype than groups B and C (p-value <0.035 and <0.009 respectively). The profile of group B patients was intermediate between normal and patients with tachycardia-mediated cardiomyopathy. I/D polymorphism of the ACE gene may account for cardiomyopathy secondary to tachycardia.