Sudden cardiac death due to lethal arrhythmia may be the initial presenting symptom of ischemic heart disease. In many cases, in the absence of trauma, a majority of these deaths will be visually inspected by a medical examiner and released with death being ascribed to atherosclerotic cardiovascular disease, coronary artery disease, arrhythmia, myocardial infarction, or a similar diagnosis. When an autopsy is performed, there may be significant cardiovascular disease but no gross or histologic evidence of an acute myocardial infarct unless the patient survived for several hours following the event. Biochemical assays of creatine kinase MB fraction (CKMB) performed on serum have been used to document myocardial injury in the absence of morphologic changes. Newly developed assays for cardiac troponin I (cTnI) may detect myocardial injury with a greater sensitivity than CKMB. A prospective study was performed on 28 autopsied patients at the Office of the Chief Medical Examiner of the state of Maryland. Subclavian blood was sampled for subsequent analysis of serum CKMB and cTnI. In 3 cases of cardiac-related death, there was insufficient plasma for analysis of both CKMB and cTnI, and only CKMB was quantitated. In 12 cases, hemolysis rendered interpretation questionable. Of the remaining 16 cases, the mean serum CKMB level was 857.9 ng/ml (n= 7) and the cTnI level was 93.4 ng/ml (n= 4) for cardiac-related deaths, compared with mean CKMB levels of 116.4 ng/ml (n= 9) and mean cTnI levels of 16.6 ng/ml (n= 9) for non-cardiac-related deaths. The differences in serum elevation of both CKMB and cTnI noted between the cardiac- and non-cardiac-related deaths were statistically significant. Serum cTnI concentrations >40 ng/ml were only noted in cardiac-related deaths. These data suggest that an elevated postmortem serum concentration of cTnI reflects ischemic heart disease and supports its use in determining cause of death. Quantitation of this analyte may prove useful when death may be due to an arrhythmia following a morphologically undetectable microinfarct.