A case-control study of determinants of multiple cancers of the upper respiratory and digestive system (URDS) was conducted using a patient cohort-nested design. We analyzed demographic and risk factor information and clinical variables related to the index cancer for 85 cases of multiple cancers and 170 controls matched on sub-site of the index cancer of the case and date of hospital admission. Follow-up information for the control group was used to infer the person-years-at-risk for the cohort of 1977 patients. URDS cancer patients experienced a 10.7 times (95% confidence interval: 8.5-13.2) higher risk of additional related cancers than the general population. Although controls had cancers of the same sites as those of cases and thus, strongly tobacco and alcohol-related, there were marked residual effects for these two risks factors. In addition, characteristics related to the extension and clinical course of the index cancer were strongly associated with the patient's risk of developing additional cancers.