The angiotensin-converting enzyme (ACE) gene is a potential candidate gene for risk of asthma, COPD, and COPD co-morbidity. In 9034 Danish adults, we determined whether individuals homozygous or heterozygous for the ACE D allele are at greater risk of asthma, COPD, or COPD co-morbidity compared with ACE II homozygous individuals. In the general population, serum ACE activity increased with the number of D alleles (Kruskal-Wallis ANOVA: II vs. ID, p < 0.001; ID vs. DD, p < 0.001); however, this did not translate into altered risk of asthma or COPD. In the general population, the odds ratio (95% confidence interval) for asthma was 1.2 (0.9-1.4) for ID individuals and 1.2 (0.9-1.5) for DD individuals compared with II individuals. In the general population, the odds ratio for COPD was 0.9 (0.8-1.1) for ID individuals and 1.0 (0.8-1.2) for DD individuals compared with II individuals. Among patients with COPD, the odds ratio for ischemic heart disease was 1.1 (0.8-1.6) for ID individuals and 1.2 (0.8-1.7) for DD individuals compared with II individuals; corresponding odds ratios for hypertension were 1.1 (0.7-1.5) and 0.8 (0.5-1.2), and for low physical activity 0.9 (0.5-1.4) and 0.7 (0.4-1.2). The results were similar upon adjustment for sex, age, smoking status, body mass index, total cholesterol, and ACE inhibitor/angiotensin II type 1 receptor blocker use. These data suggest that lifelong genetically elevated ACE activity is not a major risk factor for asthma or COPD, or for ischemic heart disease, hypertension, and low physical activity in COPD patients.