The significance of non-organ specific antibodies (NOSAs) in HCV-related chronic hepatitis is largely unclear. In this study we evaluated the prevalence of NOSAs in a non-selected population of HCV-infected subjects. One hundred and seventy anti-HCV positive and 192 anti-HCV negative sex and age-matched subjects (median age 64 years, range 7-91 years, female 68%) enrolled from the general population of a small Italian town were evaluated for NOSAs by indirect immunofluorescence on rat tissue sections and HEp-2 cells, and by counterimmunoelectrophoresis with thymus and spleen extracts as the antigen source. One hundred and sixty-three (96%) HCV-infected subjects had normal ALT serum levels and no evidence of liver disease. NOSAs were found in 31 out of 170 (18%) anti-HCV positive subjects and in 20 out of 192 (10%) controls (P = NS), with similar median titre (1:40) and range (1:40 to 1:160). Neither liver/kidney microsomal antibody type 1 nor antiactin reactivity were detected. No significant association between NOSAs and HCV genotypes was observed. In the general population, HCV-infected subjects and healthy controls have a similar prevalence of NOSAs. Without continuous liver damage HCV infection is unlikely to induce the appearance of NOSAs.