Lung cancer is the second most frequent malignancy and the leading cause of cancer-associated death worldwide. Compared with patients diagnosed at advanced disease stages, early detection of lung cancer significantly improved the 5-year survival rate from 3.3% to 48.8%, which highlights the importance of early detection. Although multiple technologies have been applied to the screening and early diagnosis of lung cancer so far, some limitations still exist so they could not fully suit the needs for clinical application. Evidence show that autoantibodies targeting tumor-associated antigens(TAAs) could be found in the sera of early-stage patients, and they are of great value in diagnosis. Methods, we identified and screened TAAs in early-stage non-small cell lung cancer(NSCLC) samples using the serological analysis of recombinant cDNA expression libraries(SEREX). We measured the levels of the 36 autoantibodies targeting TAAs obtained by preliminary screening via liquid chip technique in the training set(332 serum samples from early-stage NSCLC patients, 167 samples from patients with benign lung lesions, and 208 samples from patients with no obvious abnormalities in lungs), and established a binary logistic regression model based on the levels of 8 autoantibodies to distinguish NSCLC samples. Results, We validated the diagnostic efficacy of this model in an independent test set(163 serum samples from early-stage NSCLC patients, and 183 samples from patients with benign lung lesions), the model performed well in distinguishing NSCLC samples with an AUC of 0.8194. After joining the levels of 4 serum tumor markers into its independent variables, the final model reached an AUC of 0.8568, this was better than just using the 8 autoantibodies (AUC:0.8194) or the 4 serum tumor markers alone(AUC: 0.6948). In conclusion, we screened and identified a set of autoantibodies in the sera of early-stage NSCLC patients through SEREX and liquid chip technique. Based on the levels of 8 autoantibodies, we established a binary logistic regression model that could diagnose early-stage NSCLC with high sensitivity and specificity, and the 4 conventional serum tumor markers were also suggested to be effective supplements for the 8 autoantibodies in the early diagnosis of NSCLC.