Despite the major improvement in immunosuppressive therapy, noninvasive detection of heart graft rejection remains a challenge. As lipoproteins are involved in several immunomodulation mechanisms, we studied their proton NMR spectra in plasma from patients after heart transplantation. NMR data were compared to clinical and functional evaluation of rejection process. The total linewidth (TLW) of methyl and methylene peaks, mainly arising from lipoproteins, were significantly lower for patients without a rejection process than for patients before surgery and patients with evidences of a rejection process. When TLW values are referred to TLW on the 8th day for each patient, the sensitivity and the specificity of the test are increased, with resulting positive and negative predictive values of 90 and 91%, respectively. The results obtained on more than 400 samples from 46 patients justify the use of proton NMR spectroscopy as a clinical tool.