The existence of serum antibodies against porphyric or normal rat hepatocytes was investigated in patients with porphyria cutanea tarda and in other forms of chronic liver disease. Ten patients with porphyria cutanea tarda, 7 of them with chronic active hepatitis or cirrhosis (group 1a) and 3 without significant liver damage (group 1b), 8 patients with nonporphyric chronic active hepatitis (group 2), and 8 alcoholic cirrhotics, 3 of them with superimposed severe alcoholic hepatitis (group 3), were studied. In an antibody-dependent cell-mediated cytotoxicity test using isolated hepatocytes from normal and hexachlorobenzene-treated (porphyric) rats as targets, it was found that sera from group 1a produced high cytotoxicity against porphyric hepatocytes and low or zero cytotoxicity against normal hepatocytes (p less than 0.001). The opposite cytotoxic pattern was observed when sera from group 2 was tested. Sera from groups 1b and 3 failed to produce cytotoxicity against both targets. The cytotoxic effect on porphyric hepatocytes was significantly reduced by preincubation of serum with free uroporphyrin or by serum absorption with a sepharose-uroporphyrin immunosorbent. Immunofluorescence studies confirmed the existence of antiporphyric hepatocyte antibodies in group 1a. In conclusion, our results show that antiporphyric hepatocytes antibodies are present in some patients with porphyria cutanea tarda and indicate that hepatocellular porphyrin might be partially responsible for the antigenicity of the liver cells. The role of these antibodies in the pathogenesis of the liver lesion remains to be elucidated.