BACKGROUND: The value of elevated serum angiotensin-converting enzyme (ACE) activity in the diagnosis and follow-up in sarcoidosis is a matter of ongoing debate. This may be at least related to the insertion (I)/deletion (D) polymorphism in the ACE gene (ACE I/D). ACE activity is influenced by the ACE I/D polymorphism. As a consequence, the use of one reference interval instead of three genotype-specific reference intervals for ACE activity may lead to a less precise interpretation of ACE activity. METHODS: In order to assess whether determination of ACE activity indeed requires the ACE I/D genotype to be taken into account, we established ACE I/D-corrected reference intervals in healthy, Caucasian volunteers (n=200). In addition, ACE activities in ACE I/D genotyped patients suspected of or having sarcoidosis (n=129) were expressed as the Z-score related to ACE I/D-corrected reference intervals. RESULTS: Comparison of the Z-score with ACE activity in which ACE I/D is ignored rendered 8.5% misclassification of 'elevated' versus 'normal' ACE or vice versa. CONCLUSIONS: Our data demonstrate a convenient way to circumvent the use of three reference intervals by introducing a Z-score for ACE activity. It also illustrates the need to re-investigating the possible clinical value of serum ACE activity in sarcoidosis by considering ACE I/D.