We studied the long-term outcomes of 43 patients with chronic hepatitis C treated with one or two interferon cycles, in relation to hepatitis C virus RNA in serum and peripheral-blood mononuclear cells. After the first interferon cycle, 15 (35%) patients had normal transaminase levels, although only five of them had normal levels throughout follow-up (complete responders). After treatment, hepatitis C virus RNA was detected in serum and peripheral-blood mononuclear cells with a similar frequency among the five complete responders (60% and 40%, respectively) and the 10 responders with relapse (50% and 20%, respectively). During the follow-up of the complete responders (up to 27 mo), fluctuating viremia levels were found, as demonstrated by the intermittent serum hepatitis C virus RNA positivity. In responders with relapse serum hepatitis C virus RNA reappeared concurrent with the relapse, without changes in peripheral-blood mononuclear cells. A second interferon cycle was performed in 23 nonresponders. Six of them had normalized transaminase levels but four had relapses. After retreatment, hepatitis C virus RNA was detected in peripheral-blood mononuclear cells with the same frequency (50%) in complete responders and in responders with relapse. Loss of serum hepatitis C virus RNA was only achieved in responders with relapse. During the follow-up, half of the complete responders lost serum hepatitis C virus RNA. This marker reappeared in responders with relapse, and hepatitis C virus RNA was found de novo in PBMCs of one responder with relapse. None of the 17 nonresponders to retreatment lost hepatitis C virus RNA in serum or PBMCs during therapy.(ABSTRACT TRUNCATED AT 250 WORDS)