To compare the histological features of non-drug-induced and drug-induced coma blister, we performed histopathological and immunopathological studies of four biopsy specimens from three patients with non-drug-induced coma. These results were compared with the previously well-documented histology of drug-induced coma. The findings of the present study of non-drug-induced coma included (a) a variable degree of epidermal cell degeneration, including vacuolation of basal cells, intraepidermal blister formation with pale cytoplasm, and extensive coagulation necrosis with pale nuclei; (b) alteration of the outer root sheath of telogen follicles, ranging from focal necrosis to total coagulation necrosis, and degeneration of sebaceous gland with disappearance of the germinative cell layer; (c) secretory eccrine cells with pyknotic nuclei, vacuolation of the cytoplasm, and intercellular edema, resulting in poorly defined cytoplasm, although the nuclei of the outer basal layer were partially preserved; (d) from slight edema of the vessel wall of the venules to fibrinoid thrombosis and/or fibrinoid necrotic degeneration of arterioles and venules; and (e) deposits of immunoglobulins or complement as detected by direct immunofluorescent technique in all the three cases. One significant difference between non-drug-induced and drug-induced coma blister was the presence of fibrinoid thrombi in the lumina of non-drug-induced coma blisters. Since one of the three cases of non-drug-induced coma studied in the present report did not show thrombi in the lumina, this feature may not always be available for the differential diagnosis of these two conditions. However, fibrinoid thrombi may be a good marker for the differentiation of these two conditions, when the depth and duration of non-drug-induced coma are severe enough to induce these lesions.