AIM Our recent work suggested that circulating IgG antibodies to a linear peptide derived from p16 protein were significantly increased in patients with lung cancer. The present study was then designed to test whether such autoantibodies were also altered in esophageal cancer. METHODS An enzyme-linked immunosorbent assay was developed in-house to determine circulating IgA and IgG antibodies against p16 protein-derived antigens in 97 patients with esophageal squamous cell carcinoma (ESCC) and 226 healthy subjects. RESULTS The levels of anti-p16 IgG but not IgA antibodies were significantly higher in the patient group than the control group (t = 2.81, P = 0.0052); circulating anti-p16 IgG levels were inversely correlated with stages of ESCC (r = -0.30, df = 81, P = 0.0058) and patients with stage I of ESCC had the highest IgG level among all four stages (t = 5.25, P ≤ 0.0001, compared with control subjects). There was no correlation between the levels of IgA and IgG either in the patient group (r = -0.05, df = 86, P = 0.627) or in the control group (r = -0.1, df = 205, P = 0.146). CONCLUSION Circulating IgG autoantibody to p16 protein may be a potential biomarker for early diagnosis of esophageal cancer.