Purpose Allograft rejection remains one of the limiting factors for patient survival after HTX. Therefore, the aim of this project was to characterize the cytokine/chemokine network in heart biopsies and peripheral blood plasma after TX. The quantified cytokine/chemokine concentrations could reflect the ischemia/reperfusion response as well as rejection status of the allograft. We hypothesize that in heart biopsies with histopathological proven rejection the microenvironment is significantly altered and potentially specific cytokine/chemokine patterns could predict allograft rejection. Methods Heart biopsies (N=181 biopsies; 52 patients) and peripheral blood samples (N=35 patients) were obtained at different time points after HTX. Using luminex-based multiplex assays 50 cytokines/chemokines in tissue lysates and blood plasma were quantified. Concentrations of samples with rejection and no-rejection were compared in lysates and plasma. Correlations of tissue and plasma levels and comparison of cold static and ex situ preservation were performed. Results With regard to the rejection status we identified significant differences in lysate concentrations. CXCL9/MIG, CXCL4/MIP-1β and CXCL10/IP-10 showed significantly elevated concentrations in rejection-proven biopsies (p Conclusion We detected a core signature for biopsies with pathologically secured rejection consisting of increased concentrations of the chemokines CXCL9/MIG, CXCL3/ MIP-1α, CXCL4/MIP-1β and CXCL10/IP-10. Thus this signature clearly distinguishes from the pattern known for the ischemia/reperfusion response (i.e. elevated levels of IL-6, CXCL8, IL-10) suggesting differences in the underlying inflammatory mechanisms. Since there was no correlation between the measured protein concentrations in plasma and tissue lysates, biopsies are indispensable for the diagnosis of heart rejection.