We studied the effects of H1 and H2 histamine receptor antagonists on down regulation of contact sensitivity (CS) to dinitrofluorobenzene (DNFB). Two H2 receptor antagonists, cimetidine and ranitidine, reversed the nonspecific immunosuppression of CS induced by burns. On the other hand, these two drugs did not affect the antigen-specific suppressor T cell-mediated tolerance to DNFB induced by dinitrobenzene sulfonic acid. Two H1 antagonists did not affect the down regulation of CS induced by either tolerance or burning. The differential sensitivities to histamine2-receptor antagonists indicate that the mechanisms for nonspecific burn-induced immunosuppression are different from those for hapten-specific tolerance to DNFB.