The human MxA protein is a new specific marker for type I interferon activity both in uitro and in uiuo. In the study presented here this interferon-induced marker, as well as the 2',S'-oligoadenylate synthetases, was measured in circulating mononuclear cells from 2 1 patients with acute hepatitis A, 20 patients with acute hepatitis B and 14 patients with acute hepatitis C for determination of the activiation of the interferon system in these viral diseases. In acute hepatitis A a strongexpression (10 of 10 patients) of the MxAprotein and the 2',6'-oligoadenylate synthetase activity in peripheral-blood mononuclear cells was observed during the first 2 wk after onset of clinical symptoms. In this period the MxA protein concentrations reached levels similiar to those measured in patients treated with up to 6 x log IU interferon-a three times a week. Beyond wk 3, in eight of eight patients with hepatitis A no increased MxA protein levels were found. In contrast, peripheral-blood mononuclear cells from patients with acute hepatitis B contained either no measurable MxA protein or only slightly higher levels of the MxA protein, as did those of most patients (12 of 14) with acute hepatitis C. The MxA protein levels of both hepatitis B and C patients were significantly lower (p < 0.06) than those found in hepatitis A patients. F'urthermore, sera from 6 of 10 patients with hepatitis A, but none of 10 patients with acute hepatitis B and C, contained measurable MxA protein. This serum MxA protein may originate from interferon-exposed and subsequently damaged liver cells. These results demonstrate that endogenous interferon is produced in large amounts during the first 2 wk of hepatitis A after onset of symptoms but not thereafter. In contrast, most patients with acute hepatitis B or C produce only minor