Background: If future attempts to introduce xenografting into clinical practice prove successful, it will be essential to have a clinically relevant, reproducible grading system for vascular rejection. No formal attempt has been made to grade hyperacute or delayed vascular rejection on the basis of a review of both experimental and clinical material. Methods and Results: In an attempt to define a microscopic grading system for hyperacute vascular rejection of the heart, we reviewed the clinical and histologic findings in 112 previously personally studied experimental (n = 109) and clinical (n = 3) cardiac xenografts and allografts, most of which showed vascular rejection. The study material comprised 44 discordant xenografts, 41 concordant xenografts, and 27 allografts. We documented, analyzed, and grouped the histopathologic features together with the clinical data. We devised a grading system which allowed us to allocate each sample to one of the following two categories: grade A: unmodified hyperacute rejection; grade B: mixed hyperacute and acute cellular rejection. Both grades A and B can be subcategorized into three stages: (1) mild (initial), (2) moderate (intermediate), or (3) severe (late) stage. Conclusions: A common grading system can be applied to both hyperacute rejection and mixed (hyperacute and acute) rejection. The proposed grading system provides a basis for meaningful pathologic evaluation of hyperacute rejection.