We examined 50 non-small cell lung cancers and the matching serum from the same patients for the levels of p53 antigen. Histological sections of the tumor specimens were stained with anti-p53 specific antibodies, and the sera were tested by ELISA. We observed a correlation between the expression of the p53 protein in the tumors and the presence of circulating p53 antigen, using either a wild type-(P=0.024) or a mutant specific (P=0.007) ELISA test. The p53 serum levels were also significantly associated (P=0.019) with the extent of tumor necrosis, suggesting that circulating p53 may be derived by shedding from dead tumor cells. The levels of mutant p53 detected in the serum were significantly higher in patients with lymph node involvement (P=0.012) and with late-staged disease. (P=0.05). No association was found with tumor size and extent. Testing for serum levels of mutant p53 could provide additional prognostic information and could be used as as novel molecular diagnostic tool in the management of non-small cell lung cancer.