Background: Cardiac allograft rejection is largely an inflammatory response that, if allowed to proceed unchecked, will result in hemodynamic compromise or cardiogenic shock. Soluble mediators produced during an inflammatory response could potentially provide information regarding the initiation, progression, and outcome of a rejection episode. To test this hypothesis, we investigated the use of plasma cytokine measurements for interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor a (TNFα) in combination with measurements of soluble vascular cell adhesion molecule-1 (VCAM-1), an adhesion molecule, as a means for the detection of cardiac allograft rejection. Methods: Serial enzyme-linked immunosorbent assays were performed on plasma samples collected from 29 patients three times per week during the first 8 weeks after transplantation. Results: IL-6 plasma concentrations increased fivefold in the first week after transplantation (p < 0.001 vs pretransplantation levels) and thereafter remained at low levels for the next 6 weeks, with a small increase during the 8 weeks after transplantation (p = 0.006). In contrast, TNF-α, IL-8, and VCAM-1 levels remained low during the first 6 weeks after transplantation followed by a rise in mean VCAM-1 levels from 841 ± 38 to 979 ± 52 ng/ml at week 8. To determine the relationship of levels of each of the four soluble factors with rejection, the mean values obtained during the time interval 1 to 5 days before rejection were compared to mean values obtained during rejection and at other periods of no rejection (baseline). Cytokine levels were not predictive of rejection (no difference in levels 0 to 5 days before rejection versus baseline, p > 0.3 for IL-6, IL-8, TNF-α). However, VCAM-1 levels increased 0 to 5 days before rejection compared with baseline (914 ± 40 vs 844 ± 30ng/ml, p = 0.06). Conclusions: IL-6 levels are increased immediately after heart transplantation. Circulating IL-6, IL-8, and TNFα levels do not predict rejection during the first 8 weeks after transplantation. Soluble VCAM-1 increases within 5 days before rejection and may potentially serve as a noninvasive marker for early rejection.