Because TP53 mutations can induce an immune response and can occur early in the carcinogenic process for some tumors, p53 autoantibodies may be useful biomarkers for risk of development of cancer. Using banked serum samples from an asbestosis cohort at high risk for cancer, we demonstrate for the first time a statistically significant relationship between p53 autoantibodies and the subsequent development of malignancy (hazard ratio [HR] = 5.5, 95% confidence interval [CI] = 2.8-10.9) with a positive predictive value of 0.76 and an average lead time to diagnosis of 3.5 years. p53 autoantibodies were also significantly associated with p53 alterations in the resultant tumors (kappa = 0.78, p = 0.01).