Before the availability of serological markers for hepatitis C, the morphological features of this diagnosis, which represents most non-A, non-B hepatitis, could not be confirmed. We examined biopsy specimens from 50 patients with chronic hepatitis C and 21 patients with autoimmune chronic hepatitis. Each biopsy specimen was graded on 19 different histological features. The results indicated that at the time of biopsy, the average age of patients with chronic hepatitis C was 46 yr vs. 36 yr for autoimmune chronic hepatitis. Cirrhosis was seen more frequently in autoimmune chronic hepatitis (90%) than in hepatitis C (58%). Features more commonly observed in chronic hepatitis C were bile duct damage (91% vs. 40%), bile duct loss (91% vs. 20%), steatosis (72% vs. 19%) and lymphoid cell aggregation (follicles) within portal tracts (49% vs. 10%). Severe lobular necrosis and inflammation (76% vs. 38%), piecemeal necrosis (81% vs. 10%), multinucleated hepatocytes (29% vs. 6%) and broad areas of parenchymal collapse (76% vs. 6%) were seen more often in autoimmune chronic hepatitis. Exclusion of five patients with autoimmune chronic hepatitis who received immunosuppression before biopsy accentuated these differences. In conclusion, morphological criteria, in addition to serological data, may be useful for differentiating chronic hepatitis C from autoimmune chronic hepatitis, which histologically is a more aggressive disease.