Background Chronic infection with hepatitis C virus (HCV) has been associated in some studies with increased risk for B-cell non-Hodgkin's lymphoma (NHL). To assess this further, we conducted a case-control study in Egypt, where HCV prevalence is extremely high. Methods Cases with B-cell NHL (N = 227) were recruited from the National Cancer Institute of Cairo University, a major referral centre. Controls (N = 227) were patients with fractures being treated at the Kasr El-Aini Orthopaedic Hospital, from the same referral base as the cases, and were frequency-matched by gender, rural versus urban birthplace, and age. Subjects were interviewed about their medical history and possible risk factors, and blood samples were collected for HCV diagnostic tests. Anti-HCV and HCV RNA were determined by enzyme-linked immunoassay and reverse transcription-polymerase chain reaction, respectively. Odds ratios (OR) and 95% CI were calculated from logistic regression models. Results Overall, 42% of subjects were anti-HCV positive and 33% had HCV RNA. There was a statistically significant unadjusted association of HCV RNA with NHL (OR = 2.3, 95% CI: 1.5, 3.5), which differed slightly by gender (males: OR = 2.1, 95% CI: 1.2, 3.7 versus females: OR = 2.5, 95% CI: 1.3, 4.8). Anti-HCV without HCV RNA was not associated with case status (OR = 0.9, 95% CI: 0.5, 1.6). After adjustment for age, gender, rural versus urban birthplace, and rural versus urban current residence, the association of HCV RNA with the risk of NHL remained statistically significant (OR = 2.9, 95% CI: 1.9, 4.5). Conclusions These data support the hypothesis that NHL is a malignant outcome of chronic HCV infection.