Objectives: The presence of talc crystals in the liver has been associated with prior history of i.v. drug abuse (IVDA). Patients with hepatitis C virus (HCV) infection often deny IVDA, and many patients have no other identifiable risk factors. To evaluate the role of prior surreptitious IVDA in patients with chronic HCV infection and to assess the role of talc identification in liver tissue, an epidemiological evaluation was performed. Methods: One hundred and nine patients with chronic HCV (ALT abnormal > 6 months, HCV ELISA and recombinant immunoblot assay positive) underwent careful evaluation for risk factors potentially associated with HCV infection. All patients then had liver biopsy. Liver biopsies were reviewed by two observers to determine histological stage and were then examined by polarized light microscopy to reveal the presence or absence of typical talc crystals. Patients with discordance between history and histological findings were re-interviewed and were confronted with the information. Results: Patient interviews revealed the following risk factors: IVDA, 17.1%; blood transfusion, 24.3%; possible household/occupational exposure, 14.4%; and tattoos, 15.3%. No identifiable risk factors were noted in 28.8% of the cohort. Talc crystals were seen in 9/109 (8.3%) of liver specimens. Of this group, only two patients admitted to prior history of IVDA. Seventeen patients with an IVDA history did not have identifiable talc crystals. Follow-up phone interviews were possible with five out of seven patients,vith liver talc who had previously denied IVDA history. Of the five patients, three admitted to prior IVDA but only after being confronted with the liver biopsy evidence. Conclusions: The findings of talc crystals in liver biopsy specimens appears to be a specific, but not a sensitive, marker for prior IVDA. Identification of talc crystals from liver tissue may contribute to categorization of risk factors in patients with community-acquired HCV infection. Tattoos are an important, and frequently unrecognized, risk factor for HCV infection. Despite these findings, a significant proportion of patients still have no identifiable risk factor for HCV acquisition.