To study the role of tobacco smoking and alcohol drinking in the etiology of non-Hodgkin's lymphoma (NHL), we conducted a multicenter case-control study in Spain, France, Germany, Italy, Ireland and Czech Republic between 1998 and 2004, which included 1,742 cases of NHL and 2,465 controls matched on age, sex and recruitment area. Tobacco smoking was not associated with the risk of NHL overall or with risk of specific histological subtypes. Similarly, there was no association between alcohol drinking and the risk of NHL overall or across histological subtypes. However, a protective effect of alcohol drinking was observed among men (OR = 0.76, 95% CI = 0.62-0.93) and in non-Mediterranean countries (OR = 0.73, 95% CI = 0.61-0.86). There was no evidence of interaction between alcohol drinking and tobacco smoking in NHL etiology. The results of this large-scale European study did not support an association between tobacco and NHL and suggested a protective effect of alcohol on development of NHL for men and in non-Mediterranean countries.