Endomyocardial biopsy (EMB) remains the mainstay for the diagnosis of acute cellular rejection in cardiac transplant patients. A noninvasive alternative that would supplant or reduce the number of EMBs would be a highly desirable and cost-effective tool. To evaluate one potential alternative, a pacemaker with high resolution telemetry capabilities and two fractally coated epimyocardial leads were implanted in 30 patients at five transplant centers during the heart transplant procedure. Ventricular electrograms were recorded during intrinsic and paced activity and digitized to a laptop-based data acquisition device. Electrograms were recorded at frequent intervals and systematically on days when EMBs were performed. The electrogram data were then transferred via the Internet to a central data processing site. Clinical patient management was blinded to the electrogram results and varied considerably among the five centers. Using EMB together with clinical assessment of the transplant revealed 18 cases of clinically significant rejection beyond postoperative day 27 that required antirejection therapy. The normalized parameter values extracted from the electrogram recordings during pacing (the ventricular evoked response) that were associated with significant rejection were statistically lower (86% ± 16% versus 96% ± 22%, P < 0.005). The application of a single-threshold diagnosis model to the parameter values allowed detection of significant rejection with a negative predictive value of 98%. This analysis also showed that as many as 55% of the routine surveillance EMBs could have been eliminated had the pacemaker monitoring technique been used as a screening tool prior to EMB. A prospective study should further define the role of this technique in the detection and management of cardiac transplant patients.