Oesophageal cancer (OC) is a disease characterized by the development of malignant tumors in the epithelial cells lining the oesophagus. It demonstrates marked ethnic variation, with squamous cell carcinoma (SCC) being more prevalent in the Black population and adenocarcinoma (ADC) occurring more often in Caucasians. The etiology of this complex disease has been attributed to a variety of factors, including an excess of iron (resulting in increased tumourigenesis), oesophageal injury and inflammation (due in part to Barrett's oesophagus and smoking among others). The aim of this study was to determine if genetic variations identified in the ceruloplasmin (CP) gene (implicated in iron homeostasis) contribute to OC pathogenesis or susceptibility. The study cohort consisted of 96 unrelated OC patients from the Black Xhosa-speaking South African population and 88 population-matched control individuals. The promoter and coding regions of the CP gene were analyzed for DNA sequence variation using heteroduplex single-strand conformation polymorphism (HEX-SSCP) analysis, restriction fragment length polymorphism (RFLP) analysis and semi-automated bidirectional DNA sequencing analysis. Fourteen previously described and four novel variants were identified. Statistically significant associations were revealed for two of the novel variants with OC in this study and could, therefore, potentially contribute to disease susceptibility. In silico analysis of the region of the promoter spanning the identified variants sought to identify putative transcription factor binding sites (TFBSs) that could possibly regulate the expression of CP. To our knowledge, this is the first study to examine CP with respect to OC in the Black South African population.