The incidence of esophageal squamous cell cancer in African males in South Africa is one of the highest in the world. Because most patients present with advanced disease such that survival is poor, the identification of high-risk individuals will facilitate early disease detection. Two polymorphic triplet repeats—(CAG)n and (GGC)n—in the androgen receptor gene were evaluated as potential genetic susceptibility loci for esophageal squamous cell cancer. Shorter lengths of these alleles have been reported to be associated with increased risk for prostate cancer. Our study sample comprised African males (29 patients and 109 controls), African females (14 patients and 59 controls) and Colored males (15 patients and 58 controls) whose alleles were analyzed singly and in combination. As in prostate cancer, the short (GGC)n alleles were implicated in esophageal cancer in African males: the average allele length was significantly shorter in patients compared to controls (p = 0.018), and a short (GGC)n allele was associated with elevated risk for disease [(GGC)≤16 odds ratio (OR) 2.7, 95% confidence interval (CI) 1.14–6.36; (GGC)≤14 OR 3.3, 95% CI 1.29–8.44]. There was no evidence, however, that short (CAG)n repeat alleles increased susceptibility to the disease. When the 2 alleles were considered jointly, additional information on predisposition was gained, revealing 2 haplotypes conferring a protective effect, i.e., [(CAG)>21 (GGC)≤16] OR 0.31, 95% CI 0.11–0.88; [(CAG)≤21 (GGC)>16] OR 0.26, 95% CI 0.11–0.65. Analysis using logistic regression led to narrower CIs for the ORs and enabled presentation of a risk profile. © 2003 Wiley-Liss, Inc.