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Background: Hepatitis C virus (HCV) infection is strictly associated with mixed cryoglobulinemia, a benign B-cell lymphoproliferative disorder that may evolve to lymphoma. An increased prevalence of bcl-2 rearrangement (the t(14;18(translocation) has been shown in patients infected with HCV. Objective: To evaluate the prevalence of bcl-2 rearrangement in patients with HCV-related mixed cryoglobulinemia and patients with chronic hepatitis but no cryoglobulinemia. Design:: Prospective study. Setting: Two university hospitals. Patients: 37 consecutively recruited patients with HCV-related mixed cryoglobulinemia and 101 patients with chronic HCV infection but without mixed cryoglobulinemia. Measurements: Clinical and serologic characteristics; liver biopsy; bcl-2 rearrangement, Bcl-2 expression, and the ratio of Bcl-2 to Bax in total peripheral blood mononuclear cells and cell subgroups; and sequence analysis of the junction of bcl-2 and IgH joining segments in positive samples. Results: Rearrangement of bcl-2 was observed in 28 of 37 (75.7%) of patients with mixed cryoglobulinemia (65% of those with type III disease and 85% of those with type II disease, including 3 of 4 patients with lymphoma) and in 38 of 101 (37.6%) patients with chronic HCV infection but not mixed cryoglobulinemia (P Conclusions: Rearrangement of bcl-2 was found with increased frequency in patients with chronic HCV infection and mixed cryoglobulinemia. The frequency was greatest in patients with type II mixed cryoglobulinemia. The high ratio of Bcl-2 to Bax in patients with bcl-2 rearrangement and disappearance of the rearrangement with antiviral therapy suggest that the translocation is associated with the antiapoptotic function of bBcl-2 and that HCV infection is linked to inhibition of B-cell apoptosis.