Tobacco smoking is a well-documented risk factor for several cancers, but the role of cigarette smoking in the etiology of non-Hodgkin lymphoma (NHL) is inadequately understood. Hepatitis C virus (HCV) has been associated with NHL, but the interaction between HCV and smoking habits has not yet been studied. Between 1999 and 2002, we conducted a case-control study on the association of HCV, smoking habits and NHL in 2 areas of northern and southern Italy. Cases were 225 consecutive patients (median age, 59 years) with a new diagnosis of NHL that were admitted to reference and general hospitals. Controls were 504 patients (median age, 63 years) admitted to the same hospitals as cases, for a wide spectrum of acute, nonneoplastic, nonimmune-, nor tobacco-related conditions. Current, heavy smokers (≥20 cigarettes/day) had an odds ratio (OR) of NHL of 2.10 (95% confidence interval, CI: 1.07–4.12) compared to never smokers. The association between smoking and NHL was consistent across strata of sex and age. Compared to never smokers, current smokers of ≥20 cigarettes/day had ORs of 1.14 (95% CI: 0.37–3.56) for B-cell-low-grade, 2.10 (95% CI: 0.94–4.67) for B-cell-intermediate and high-grade, and 25.84 (95% CI: 1.95–342.17) for T-cell NHL. The effect of tobacco smoking and HCV were independent on the relative risk, leading a 4-fold elevated risk in current smokers HCV positive subjects. Tobacco smoking and hepatitis C virus (HCV) have been associated to non-Hodgkin lymphoma (NHL), but the interaction between HCV and smoking habits has not yet been studied. Our study confirms that tobacco is related to NHL, and reports on the combined effect of tobacco smoking and HCV. Infection acted together according to a multiplicative model, leading to a 4-fold elevated risk in current smokers HCV positive subjects. © 2005 Wiley-Liss, Inc.