PurposeStudies from our laboratory have reported 14 tumor antigens that elicit an autoantibody response in patients with cancer of the gingivobuccal complex (GBC) In this study, utility of the autoantibody response has been evaluated for prognosis of cancer of the GBC.Experimental designAutoantibody response was evaluated using immunoproteomics and the prognostic significance was assessed by Kaplan‐Meier survival and multivariate analysis.ResultsAutoantibody response against α‐enolase isoforms a, b, and c and Hsp70 was detected in 27, 53, 64, and 26% of the 78 patients, respectively. Patients positive for autoantibody response to α‐ENO and Hsp70 individually and in combination, showed significantly reduced disease‐free survival (DFS) compared to those who do not show autoantibody response to either of them. Further the patients, who exhibit autoantibody response to α‐ENO and Hsp70 in combination with nodal involvement and/or differentiation status, have significantly lowered DFS. The relative risk of recurrence is 3.41 for patients who exhibit autoantibody response to both the antigens.Conclusions and clinical relevanceAutoantibody response against α‐ENO and Hsp70 provides an additional parameter and may be utilized along with nodal involvement and differentiation status for better prognosis of cancer of GBC.