The aim of the present study was to evaluate the possible relationship between tobacco smoking and alcohol drinking and the anatomical sites of squamous cell carcinoma (SCC) of the lip and oral cavity. For this purpose, a case-case study has been performed in 690 patients. The study was focused on the relative risk (RR) or developing SCC at various (sub)sites, for smokers and drinkers of alcohol (divided into moderate and heavy users) relative to non-smokers and non-drinkers. Estimates of ratios of these relative risks were obtained. The relative risk associated with tobacco smoking, adjusted for the use of alcohol, appeared to be highest for SCC in the retromolar area, followed by the floor of mouth, whereas the lowest RR was found in the cheek mucosa. For alcohol drinking, adjusted for tobacco smoking, RR of SCC of the floor of mouth was significantly higher than for the tongue, whereas the RR of SCC of the cheek appeared to be lowest. Furthermore, this study suggests that the contrasts between relative risks, observed by anatomical site of oral SCC, are more pronounced for tobacco smoking than for the use of alcohol. The possible local and systemic factors responsible for these variations of susceptibility for tobacco and alcohol within the oral cavity are discussed.