We studied hepatitis C virus carriers with normal liver function to evaluate the histological features of their livers and the replicative levels of hepatitis C virus. Liver biopsies were performed in 22 hepatitis C virus carriers with persistently normal ALT levels. Hepatitis C virus RNA in serum was quantified with a competitive assay that combined reverse transcription and the polymerase chain reaction, which is based on co-amplification of the target RNA with known amounts of synthetic mutated RNA. Three patients had normal livers on histological study, whereas the other 19 had chronic persistent hepatitis, with lymphoid infiltrates or aggregates in portal tracts commonly observed but intralobular inflammatory changes absent or minimal. The titer of hepatitis C virus RNA (logarithmic transformed copy number per milliliter of serum) varied from 4.0 to 8.0 (mean +/- S.D.: 6.3 +/- 1.1); it was significantly lower in the three patients with normal livers (4.3 +/- 0.2) than in those with chronic persistent hepatitis with mild (6.4 +/- 0.8, n = 11) or moderate (7.1 +/- 0.5, n = 8) portal inflammation. The titer of hepatitis C virus RNA was correlated with the total score (r = 0.68) and the score for portal inflammation (r = 0.68) in the histological activity index. These results indicated that there seem to be "healthy carriers" of hepatitis C virus with extremely low levels of viral replication. However, in most hepatitis C virus carriers with persistently normal ALT levels, there are inflammatory changes in the portal tracts, with severity depending on the replicative levels of hepatitis C virus.