To test whether automated measurements of cortisol-induced changes in the leukocyte differential can provide an early marker of myocardial infarction, especially when combined with the rapid creatine kinase-MB isoenzyme. A prospective, blinded study of these measurements at the time of initial assessment in the emergency department. Large multispecialty clinic hospital. 511 consecutive patients presenting to the emergency department with chest pain. One hundred twenty-seven patients with infection, trauma, or metastatic cancer or receiving myelosuppressive or glucocorticoid therapy were excluded. Automated leukocyte differentials, rapid creatine kinase-MB levels, cortisol levels, and routine clinical measurements. Of 69 patients with myocardial infarction, only 39% had diagnostic electrocardiographic ST-segment elevation. ST-segment elevation had a specificity of 99% and a positive predictive value of 93%. A relative lymphocytopenia (lymphocyte decrease 4.7 ng/mL) was more sensitive than ST-segment elevation (sensitivities of 58% and 56%, respectively) but less specific (specificities of 91% and 93%, respectively). The presence of both a relative lymphocytopenia and an elevated rapid creatine kinase-MB level had a sensitivity of 44%, a specificity of 99.7%, and a positive predictive value of 97% (95% CI, 80% to 99%). Both a relative lymphocytopenia and an elevated rapid creatine kinase-MB level were independent (P < 0.001) predictors of infarction in patients without ST-segment elevation. If myocardial infarction was suspected by the presence of both abnormal markers or ST-segment elevation, the sensitivity for early diagnosis increased from 39% (ST elevation alone) to 65% (CI, 52% to 76%); the specificity was 99%; and the positive predictive value was 94% (CI, 82% to 98%). The presence of both a relative lymphocytopenia and an elevated rapid creatine kinase-MB level was an accurate early marker of myocardial infarction that appeared to improve the sensitivity of early diagnosis compared with that of ST-segment elevation alone.