OBJECTIVE The etiology of chronic obstructive lung disease (COPD) is unclear. It is supposed to be the product of an exogenous antigenic stimulus, such as tobacco smoke, and an endogenous genetic susceptibility. The angiotensin-converting enzyme (ACE) gene contains a polymorphism based on the presence (insertion [I]) or absence (deletion [D]) of a 287-bp nonsense domain, resulting in three different genotypes (II, ID and DD). The aim of the study was to find out whether the ACE gene polymorphism can determine the course of COPD. METHODS We genotyped 152 Caucasian patients with COPD and 158 healthy controls for the ACE (I/D) polymorphism. We divided the COPD group into one group of 64 patients with a stable course of disease, defined as less than three hospitalizations over the last three years due to COPD, and another group of 88 patients with an instable course with more than three hospitalizations. RESULTS The I-allele was significantly associated with an increased risk for COPD in a dominant model (OR 1.67 (95% CI 1.00 to 2.78), p=0.048), but not in a recessive or co-dominant model. Moreover, the I-allele of ACE (I/D) was significantly increased in patients with a stable course of COPD (p=0.012) compared with controls. In a dominant model (II/ID v DD) we found an even stronger association between the I-allele and a stable course of COPD (OR 3.24 (95% CI 1.44 to 7.31), p=0.003). CONCLUSIONS These data suggest that the presence of an ACE I-allele determines a stable course of COPD.