The functional significance of alterations in expression of tumour-suppressor gene p53 and 70-kDa heat-shock protein (HSP70) in eliciting p53-specific humoral response in oral-cancer patients is not yet known. In this study, p53 auto-antibodies were analyzed in sera from oral-cancer patients by immunoblotting and results were correlated with clinicopathological features of the patients as well as with the levels of HSP70, p53 and p53-HSP70 complexes in matched patients' tumour tissue, for determining their diagnostic/prognostic significance and relationship to survival. Circulating anti-p53 antibodies were observed in 7 of 30 cancer patients and 3 of 25 patients with pre-malignant lesions. Over-expression of p53 protein in matched oral lesions was observed in 22 of these 30 cancer patients and 14 of 25 patients with dysplastic lesions. No detectable levels of p53 protein or anti-p53 antibodies were observed in normal subjects (15 cases). Elevated levels of HSP70 were observed in 23 of these 30 oral tumours and 17 of 25 dysplastic lesions. All the anti-p53-antibody-seropositive cases showed elevated levels of p53 and HSP70 proteins, as well as formation of p53-HSP70 complexes, in matched dysplastic or malignant lesions, suggesting that these molecular alterations may be early events in oral tumorigenesis and are implicated in eliciting p53-specific humoral immune response in these patients. Anti-p53-antibody-seropositive cases showed poor prognosis and significantly decreased overall disease-free survival in comparison with the seronegative cases. Detection of circulating anti-p53 antibodies may serve as a useful non-invasive marker for identifying oral tumours having poor prognosis.