BACKGROUND: This study aimed to investigate the efficiency of combining tumor-associated antigens (TAAs) and autoantibodies in the diagnosis of lung cancer. METHODS: The serum levels of TAAs and seven autoantibodies (7-AABs) were detected from patients with lung cancer, benign lung disease and healthy controls. The performance of a new panel by combing TAAs and 7-AABs was evaluated for the early diagnosis of lung cancer. RESULTS: The positive rate of 7-AABs was higher than the single detection of antibody. The positive rate of the combined detection of 7-AABs in lung cancer group (30.2%) was significantly higher than that of healthy controls (16.8%), but had no statistical difference compared with that of benign lung disease group (20.8%). The positive rate of 7-AABs showed a tendency to increase in lung cancer patients with higher tumor-node-metastasis (TNM) stages. For the pathological subtype analysis, the positive rate of 7-AABs was higher in patients with squamous cell carcinoma and small cell lung cancer than that of adenocarcinoma. The levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment 211 (CYFRA 21-1) were significantly higher than that of benign lung disease and healthy control groups. An optimal model was established (including 7-AABs, CEA and CYFRA21-1) to distinguish lung cancer from control groups. The performance of this model was superior than that of single markers, with a sensitivity of 52.26% and specificity of 77.46% in the training group. Further assessment was studied in another validation group, with a sensitivity of 44.02% and specificity of 83%. CONCLUSIONS: The diagnostic performance was enhanced by combining 7-AABs, CEA and CYFRA21-1, which has critical value for the screening and early detection of lung cancer.