Carcinomas of the upper aero-digestive tract (UADT) are among the most common neoplasms, particularly in developing countries. The generally poor prognosis for UADT cancer patients is further complicated by the occurrence during follow-up of additional cancers of the same or related sites. Proper quantification of the incidence of these second cancers and characterization of their risk factors have been plagued with methodological difficulties. The effects of tobacco and alcohol consumption vary with anatomic site, which requires that matching or adjustment by site be performed in any comparisons between single primary and multiple primary patients. Clinical variables, such as disease extension, treatment and survival, also influence risk of second malignancies. However, these parameters are also strongly interrelated, which makes it difficult to characterize their individual associations with risk or to control for their confounding effects when examining other variables. These shortcomings should be taken into consideration in the design of studies searching for genetic and other inter-individual variations in susceptibility to multiple UADT malignancies.