OBJECTIVE Although biochemical and virological responses to interferon-alpha therapy for chronic hepatitis C virus infection have been extensively studied, long-term changes in liver histology have not been well documented. METHODS We retrospectively analyzed 105 paired liver biopsy specimens taken before and after treatment from 93 patients who persistently showed biochemical remission and an absence of viremia for up to 68 months. RESULTS The grading scores for necroinflammatory and fibrotic activity in the liver biopsy specimens decreased significantly after interferon-alpha therapy. Histological scores graded according to Knodell's components improved significantly in every category after interferon-alpha therapy. However, inflammatory cell infiltrates remained within the portal tracts for long periods; necroinflammation in the periportal and lobular regions were absent in most of the post-therapy specimens. The cumulative disappearance rate, calculated using the Kaplan-Meier method, was significantly lower for portal inflammation than for periportal or lobular necroinflammation but was equivalent to that for histological disease activity. On univariate analysis, age and fibrosis at the onset of treatment were significant factors influencing the response of histological disease activity to interferon-alpha therapy (p=0.025 and 0.049, respectively). Using Cox's proportional hazard analysis, age was the only significant independent predictor of histological response to treatment (p=0.035). CONCLUSIONS Clinical remission of chronic hepatitis C virus infection is associated with histological resolution of necroinflammation in the periportal and lobular regions. Host-related factors are likely to influence whether early remission of inflammation after interferon-alpha therapy occurs.