Giant cell myocarditis (GCM) is a rare, rapidly fatal myocarditis with histologic features that have some similarities to cardiac sarcoidosis (CS). The natures of the inflammatory filtrates of GCM and CS have not been systematically compared. We retrospectively compared the immunohistochemical and light microscopic findings at autopsy in eight hearts with GCM and seven hearts with CS. The patients with GCM were six women and two men (mean age, 50 ± 13 yr) who presented with congestive heart failure with a mean duration of 46 days until death (range, 1-180 d). We observed three histologic phases, often within a single heart. The acute phase (seven cases of eight) demonstrated an extensive infiltrate of lymphocytes and eosinophils with plentiful macrophages and macrophage-derived KP-1 positive giant cells (GCs) associated with myocytic necrosis. No granulomas were identified. A healing phase (three cases of eight) showed granulation tissue, moderate macrophagic GCs, and scattered KP-1-negative myogenic GCs. A healed phase (three cases of eight) showed dense scar with no GCs. Macrophagic GCs were present preferentially in areas of myocytic damage and were never present in epicardial fat. The majority of lymphocytes were T cells, with a predominance of CD8 cells, The seven patients with CS were men (mean age, 44 ± 18 yr). Six patients presented with sudden cardiac death and one with congestive heart failure. The histologic patterns were similar in all seven, with scattered interstitial and epicardial five cases of seven) granulomas composed of KP-1 positive macrophages and macrophagic GCs and T lymphocytes, which were predominantly CD4 cells. Necrosis, myogenic GCs, and significant numbers of eosinophils were absent. Dense scarring was present in five cases of seven. GCM is characterized by myocytic destruction mediated by cytotoxic T cells, macrophagic GCs, and eosinophils. In contrast, CS is an interstitial granulomatous disease without myocytic necrosis.