Although tobacco smoking has long been recognized as a major risk factor for cancer of the upper aero-digestive tract (UADT, i.e., oral cavity, pharynx, larynx, and oesophagus), very few studies have provided estimates of the effect of very low tobacco consumption. Step-functions have been the common statistical methods for risk estimates, but the choice of reference category and of interval cutpoints influence the results, especially when data are sparse. In the present analysis, the dose-response relationship between UADT cancers and tobacco smoking was evaluated through logistic regression spline models. We included 1,241 UADT male cases and 2,835 male controls pooled from a large series of case-control studies conducted in northern Italy and in the Swiss Canton of Vaud during the last 2 decades. For cancers of the pharynx, larynx and oesophagus, the risk steadily increased with number of cigarettes/day. The risk of oral, pharyngeal and oesophageal cancers was significantly higher in smokers than in nonsmokers beginning with as low as 2 cigarettes/day. The effect of tobacco smoking at low levels seemed less evident for laryngeal cancer since the raise in risk begun with 6 cigarettes/day. In conclusion, for all the examined UADT sites, a monotonic dose-response relationship between cancer risk and cigarette smoking emerged. The excess of risk among people smoking 2 cigarettes/day highlights the absence of any harmless level for cigarette smoking, and it further supports the need of public health programs against tobacco smoking.