The incidence, morphology, and immunoreactivity of endomyocardial lymphocytic infiltrates (ELIs) were studied to define the lesion more precisely, gain insight into its cause, and elucidate a possible relationship between ELIs and other lymphoproliferative lesions known to be associated with cyclosporine treatment of transplant recipients. We found ELIs in 166 (14.4%) of 1152 biopsy specimens from cyclosporine-treated patients with cardiac transplants, with 78.6% of those patients having at least one ELI. The ELIs ranged in size from 0.007 to 1.89 mm2 and were predominantly T-lymphocyte infiltrates with foci of polyclonal B lymphocytes (follicular center type). Macrophages and plasma cells were located at the interface between the ELI and myocardium. The infiltrate extended into the myocardium in approximately 50% of cases and was associated with severe, local myocyte injury. The morphologic and immunohistochemical appearance was distinct from that of acute rejection and consistent with an early lymphoproliferative lesion of the type associated with Epstein-Barr virus and cyclosporine therapy.