In a long term experiment, a systematic analysis was made of the cellular reaction of the myocardium and the lymphatic system to application of antigenic substances. Several groups of mice received single or repeated injections of human serum, serum from rabbits with antiheart antibodies, mouse spleen cells immunized to myocardium, and human or mouse cardiac homogenate with and without incomplete or complete Freund's adjuvant. After injection of human and mouse heart homogenate, hypertrophy of myocardial cells was the first alteration seen; then followed focal myocarditis and after 10 months, interstitial fibrosis. Simultaneously, in the lymphorecticular tissue, there was marked proliferation of reticulum cells, lymphocytes, and plasma cells, as well as an enlargement of secondary follicles. All the animals produced antibodies to the injected antigens. Following injection of human serum or serum from rabbits with cardiac specific antibodies or spleen cells, no morphological changes were seen in the hearts.