Background: Several studies from Europe have reported a high prevalence (9% to 32%) of chronic hepatitis C virus (HCV) infection in patients with B-cell non-Hodgkin lymphoma. It has been suggested that HCV plays a role in the pathogenesis of B-cell non-Hodgkin lymphoma. Objective: To determine the prevalence of HCV infection in patients with B-cell lymphoma in the United States. Design: Controlled, cross-sectional analysis. Setting: University medical center. Patients: 120 patients with B-cell lymphoma (78% were Hispanic, 9% were black, 7% were Asian, and 6% were white), 154 patients with other malignant hematologic conditions (control group 1), and 114 patients with nonmalignant conditions (control group 2). Measurements: Samples were tested for antibodies to HCV by enzyme-linked immunosorbent assay. Hepatitis C virus RNA was detected by reverse-transcription polymerase chain reaction. Genotyping for HCV was done with genotype-specific primers from the HCV core region. Results: infection with HCV was detected in 26 patients (22% [95% CI, 15% to 30%]) with B-cell lymphoma compared with 7 of 154 patients (4.5%) in control group 1 and 6 of 114 patients (5%) in control group 2 (P < 0.001). Risk factors for HCV infection were present in 15 patients (60%) with B-cell lymphoma and occurred a median of 15 years before diagnosis of lymphoma. Monocytoid B-cell lymphoma was the most common type of lymphoma found in HCV-positive patients (23% compared with 7% in HCV-negative patients) (P = 0.034). Conclusions: The prevalence of HCV infection was higher in patients with B-cell non-Hodgkin lymphoma than in controls. The possible role of HCV in the pathogenesis of B-cell lymphoma warrants further investigation.