The aim of this study to determine whether serum p53 protein and antibodies are associated with malignant tumors. A case-control study was conduct in 569 patients with various types of malignant tumors and 879 healthy controls. Serum p53 protein and antibodies were analyzed by enzyme-linked immunosorbent assay (ELISA).The rate of positive p53 protein in patients with various malignant tumors was 4.22% compared with 0.34% in healthy controls (P < 0.001). The rate of anti-p53 antibodies in patients with various malignant tumors was 14.59% compared with 1.02% in healthy controls (P < 0.001). The adjusted odd ratio (OR) for p53 protein was 17.55 (95% CI = 4.98-61.94). The adjusted odd ratio for anti-p53 antibodies was 14.27 (95% CI = 6.75-30.16). The study strongly suggested that serum p53 protein and antibody are associated with increased cancer risk and can be used as early serological markers in the diagnosis of malignancies tumors.