The activities of two histamine-metabolizing enzymes, histamine-N-methyltransferase (HMT) and diamine oxidase (DAO), were examined in various types of experimentally induced cutaneous inflammations in guinea pigs. In intact guinea-pig skin, the specific activities of HMT and DAO were 24.8 +/- 1.7 pmol/min per milligram of protein or 0.930 +/- 0.097 pmol/min per milligram of the wet weight of skin specimen, and 6.0 +/- 0.7 pmol/min per milligram of protein or 0.189 +/- 0.011 pmol/min per milligram of the wet weight, respectively. Both enzyme activities were markedly reduced in skin lesions of the Arthus reaction (P less than 0.005), while those in dinitrochlorobenzene allergic dermatitis, croton-oil dermatitis, and the intact areas in Arthus-reaction-induced animals were almost within the normal limits. The activity of HMT decreased linearly with time from the onset of the Arthus reaction, reaching about 20% of the control activity at 48 h; the activity of DAO decreased even from the early stages of the reaction, and this decrease continued throughout first 48 h of the reaction. These results suggest that impaired histamine metabolism in the skin lesions of the reaction plays a distinct role in the formation and development of the Arthus reaction.