The rejection of a transplanted heart leads to an accumulation of mononuclear cells in the cardiac tissue and to reactions of the antigen-recognizing cells with the foreign tissue. Consequently, during rejections immunologic changes, such as the number of mononuclear cells and the patterns of mononuclear cell subpopulations, should be detectable by analysis of mononuclear cells from the coronary sinus of transplanted hearts. Seventy-nine endomyocardial biopsies were performed in 37 patients. Severity of graft rejection was classified by the Billingham scheme. Thirty-two biopsy specimens showed no rejection, 33 mild, and 14 moderate rejection. After endomyocardial biopsy the coronary sinus was catheterized under x-ray guidance. Heparinized blood samples were obtained from the coronary sinus and the right atrium, and mononuclear cell counts and subpopulation pattern were compared. Patients without rejection and patients with mild rejection showed no significant differences in the patterns of mononuclear cell subpopulation identified in right atrium blood. However, a significant (1.56-fold) increase of mononuclear cells was assessed in the CS blood (p less than 0.01). Moderate rejections showed a 4.2-fold augmentation of mononuclear cells in the coronary sinus (p less than 0.005) compared with nonrejections. In addition, the T-helper/inducer (CD4) percentage increased from 27.1% in the right atrium to 41.2% in the coronary sinus (p less than 0.005), natural killer cells (CD16) from 17.7% to 31.8% (p less than 0.005), and the interleukin 2 receptor-bearing cells from 6.6% to 15.3% (p less than 0.005). Percentage of pan-T cells (CD3), T-cytotoxic/suppressor cells (CD8), and monocytes (CD14) showed no statistically significant changes. These findings correlated with grading according to endomyocardial biopsy. Using the ratio of values obtained from cells of the coronary sinus and the right atrium rendered the coronary sinus immunologic monitoring independent of changes in the administered immunosuppressive regimen. The specificity of the described method was as good as that of endomyocardial biopsy. It is concluded that the discrimination of the patterns of mononuclear cell subpopulations from right atrium versus coronary sinus blood samples is highly sensitive and allows the correct diagnosis of graft rejection within 1 to 2 hours.