The purpose of the present study was to investigate the clinical usefulness of the detection of serum p53 antibodies (p53 Abs) in patients with oral squamous cell carcinoma (SCC). Preoperative values of p53 Abs were measured by enzyme-linked immunosorbent assay in 113 patients with primary oral SCC and seropositive patients were reevaluated postoperatively. The positivity rate of p53 Abs was 16%, and the 5-year survival rate of patients positive for p53 Abs was significantly lower than that of patients negative for p53 Abs (56.2% vs. 80.7%; P = 0.018). The preoperative presence of p53 Abs was found to be an independent prognostic factor in a multivariate analysis (P = 0.028, hazards ratio = 3.34), and its positivity was significantly related to secondary cervical lymph node metastases (P = 0.029). Six of nine patients who remained seropositive for p53 Abs through the disease course and the one with seropositive reversion from temporary negative status developed treatment failure. Therefore, the detection of p53 Abs in the serum of patients with SCC may be a useful prognostic marker.