To compare the separate and combined effects of alcohol drinking and smoking between the 2 sites, we evaluated 274 men with oral cancer, 364 with pharyngeal cancer and 1,254 controls, frequency-matched for age and area of residence, from Italy and Switzerland. Extremely elevated risk increases for oral cancer (odds ratio, OR = 228) and pharyngeal cancer (OR = 100) were found for the highest joint level of drinking (>/=77 drinks/week) and smoking (>/=25 cigarettes/day). Ratios of ORs between oral cancer and pharyngeal cancer vs. controls, obtained by polytomous logistic regression, suggested that the risk increase for oral cancer was about 2-fold greater than that for pharyngeal cancer at each combined level of smoking and drinking, except at low levels of drinking in smokers. A clear departure from risk difference additivity was present for both oral and pharyngeal cancer in individuals heavily exposed to both factors versus non-smoking abstainers/light drinkers. Our findings thus help explain observations from descriptive epidemiology that, if smoking level in a population does not change substantially, but alcohol consumption increases, increase in oral cancer would be greater than at any other site in the upper aero-digestive tract, including cancer of the pharynx.