Cancer of the proximal digestive tract is associated with tobacco smoke and ethanol exposure. The UDP-glucuronosyltransferase (UGT) 1A7 is a detoxifying enzyme capable of tobacco-borne carcinogen detoxification and cellular protection and has been implicated as a cancer risk gene. In this study, UGT1A7 expression is demonstrated in oral, esophageal, and gastric tissue, which are the principle sites of proximal digestive tract cancer. Genomic DNA from the blood of 76 patients with esophageal, orolaryngeal and gastric cancer as well as from 210 healthy blood donors was analysed for the presence of UGT1A7 polymorphisms by sequencing and temperature gradient gel electrophoresis. Wild type UGT1A7 alleles were equally distributed between controls (19 %) and cancer patients (22 %). However, the UGT1A7*3 allele combining W208R, N129K and R131K missense mutations and exhibiting substantially reduced carcinogen detoxification activity was significantly associated with proximal gastrointestinal cancer and identified as a risk allele present in 32 % of cancer patients and 19 % of controls (P = 0.0008, OR 2,02 (95 %-CI 1.33-3.07)). We identify the significant association of the UGT1A7*3 allele encoding a low catalytic activity protein as a risk gene in proximal digestive tract cancer and as a potential marker for cancer susceptibility.