Although increased serum creatine kinase (CK) activity in the presence of an increased level of myocardial-specific isoenzymes (CKMB) has been strongly associated with acute myocardial infarction, the significance of an increased serum CKMB level in the presence of a normal total CK level is uncertain. In 335 consecutive patients suspected of having an acute myocardial infarction and 71 control subjects, peak serum CKMB and CK levels were correlated with the presence of other clinical criteria for acute myocardial infarction: (1) typical chest pain, (2) increased myocardial lactate dehydrogenase (LDH1/LDH2), (3) acute electrocardiographic changes (new or ST-T wave changes with evolution), and (4) an elevated CKMB level on 2 or more determinations or a typical CK curve. No control subject had an increase in CK or CKMB or any of the 4 criteria for myocardial infarction. Of the 176 subjects with normal CK and normal CKMB (Group 1), only 11% had more than a single criterion, and none had more than 2 criteria consistent with myocardial injury. In contrast, of the 83 with elevated CK and CKMB levels (Group 2), 93% had 2 or more and 81% had 3 or more of the 4 criteria. Of the 63 patients with elevated CKMB but a persistently normal CK (Group 3), 65% had 2 or more criteria for acute myocardial infarction and 77% had subendocardial electrocardiographic changes; these patients resembled those with both elevated CK and MB. The phenomenon of elevated CKMB with normal CK occurred in 20% of the patients aged greater than or equal to 70 years but in only 10% of the younger group (p less than 0.01). These findings suggest that elevated CKMB with normal CK likely represents definite myocardial injury, is more likely represents definite myocardial injury, is more common in the elderly, and should be considered part of the spectrum of nontransmural myocardial infarction.