Using data from the Third National Health and Nutrition Examination Survey (United States, 1988-1994), we compared clinical phenotypes of hepatitis C virus (HCV)-seropositive and seronegative adults aged 20-89 years with hyperglycemia (impaired fasting glucose (IFG) or type 2 diabetes, n=3566 including 86 with HCV). Seroprevalence was higher among younger persons (3.4% for ages 20-59 versus 0.9% for ages 60-89, p=0.002), while traditional correlates of diabetes (hypertension, coronary heart disease) were more prevalent among older persons (both comparisons, p<0.0001). To prevent confounding by age, younger and older persons were analyzed separately. In both age groups, HCV was associated with signs of hepatic impairment and B-cell clonal expansion (higher alanine aminotransferase (ALT) and serum globulin, lower total cholesterol and platelet count). Only among younger persons, however, was HCV also associated with a marker for advanced hepatic fibrosis (elevated serum ferritin) and absence of the classical diabetic phenotype (overweight, coronary heart disease). In addition, among younger persons, HCV was currently associated with family history of diabetes, positively in persons with diabetes and inversely in those with IFG, suggesting that family history of diabetes may serve as a cofactor for progression from HCV-associated IFG to diabetes.