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To test the hypothesis that the angiotensin converting enzyme (ACE) genotype is associated with chronic beryllium disease (CBD) and disease severity, we studied 50 cases of CBD and compared their ACE genotype to that of two different control groups, consisting of: (1) 50 participants from a beryllium machining facility; and (2) 50 participants from a non-beryllium-associated workplace. We found no statistically significant difference in the frequency of the I or D allele or of the DD genotype among cases of CBD and either control group. The odds ratio (OR) for the CBD DD genotype as compared with the non-DD genotype was 1.58 (95% confidence interval [CI]: 0.68 to 3.66, p = 0.12) for the beryllium-exposed control group, and 1.09 (95% CI: 0.48 to 2.46, p = 0.56) for the non-beryllium-exposed controls. We found an association between serum ACE activity and the ACE genotype, with DD cases having the highest median serum ACE activity (p = 0.005). We evaluated the beryllium lymphocyte proliferation test (BeLPT), bronchoalveolar lavage (BAL) cell components, chest radiography, pulmonary function test results, and exercise physiology in our CBD cases. No statistically significant associations with these disease markers were found for the CBD cases with the DD genotype. Although the difference was not statistically significant, the DD cases had a shorter median duration of exposure to beryllium before diagnosis of CBD, and tended to have a weaker response in their blood and BAL BeLPT than did the non-DD cases. These findings may indicate that the ACE genotype is important in the immune response to beryllium and in progression to beryllium disease.