Esophageal cancers (ECs) show poor prognosis and decreased overall survival due to late diagnosis and ineffective therapeutics, urging the introduction of novel biomarkers to aid disease management. The levels of sialyl-Lewis(a) antigen (sLe(a)) are frequently increased in digestive tumours, which has been explored in serological non-invasive prognostication (CA19-9 test); however, with low sensitivity and specificity. Autoantibodies against cancer antigens are considered the next generation biomarkers, as they are present in circulation long before tumour-associated proteins. Based on these observations we have mined the serum of EC patients (n = 7) for antibodies against sLe(a)-glycosylated protein species. All EC were positive for sLea, irrespectively of their histological nature but only two patients showed elevated CA19-9. Moreover, IgG titers, with emphasis on IgG1, were elevated in EC patients in comparison to the control group. SLea-glycoproteins were then extracted from tumours of patients with negative CA19-9, isolated by immunoprecipitation and blotted with patients IgG. Autoantibodies against sLea-glycosylated proteins were detected in all cases. Different SLea-glycoproteins were observed for tumours of distinct histological natures, which now require identification and validation in larger patient sets. This preliminary data suggests that antoantibodies against sLea glycosylated proteins hold potential for non-invasive diagnosis in CA19-9 negative cases and sets the rational for future immunoproteomic studies envisaging highly specific EC biomarkers.