For individuals testing anti-HCV positive but negative for HCV RNA in serum, diagnosis remains unclear. Debate exists over whether these individuals have resolved infection or have similar clinical, histological, and virological profiles as serum PCR-positive individuals. The aim of this study was to assess the significance of histological changes in the liver of 33 serum PCR-negative women by investigation of clinical, histological, and intrahepatic HCV RNA status. For comparison, clinical and histological data from 100 serum PCR-positive women is presented. Viral RNA status was determined in snap-frozen liver biopsies using a sensitive nested PCR with an internal control. Although serum PCR-positive and -negative individuals shared similar age at diagnosis, source, and duration of infection, they differed from a clinical, histological, and virological perspective. Mean serum ALT levels were significantly lower in serum PCR-negative women (27.4 IU/L +/- 18 vs. 58.7 IU/L +/- 40 P <.001). Similarly, although inflammation (82%) and mild fibrosis (15%) were observed in PCR-negative biopsies, the mean HAI/fibrosis scores were significantly lower than in serum PCR-positive biopsies (1.9 +/- 1.5/0.15 +/- 0.4 vs. 4.2 +/- 1.4/1.1 +/- 1.3, respectively). Finally, HCV RNA was not detectable in serum PCR-negative liver biopsies but was detectable in all serum PCR-positive control biopsies. In conclusion, serum PCR-negative individuals may have mild histological abnormalities more suggestive of nonspecific reactive changes, steatosis or nonalcoholic steatohepatitis rather than chronic HCV, even when significant antibody responses are present in serum. Negative serum PCR status appears to reflect cleared past-exposure in liver.