Objective To investigate the application values of pulmonary tumor⁃associated autoantibodies (TAAbs) combined with serum tumor markers and CT imaging indices in the differentiation between benign and malignant ground⁃glass nodule (GGN) and in the assessment of malignant GGN invasion. Methods A retrospective analysis was conducted on the clinical data of 213 GGN patients, therein there were 68 cases of benign GGN (the benign group), whereas 145 cases of malignant GGN (the malignant group). Seven TAAbs in terms of tumor protein p53 (p53), SRY⁃box transcription factor 2 (SOX2), G antigen 7 (GAGE7), GBU4-5, protein gene product 9.5, MAGE family member A1, CAGE, and carcinoembryonic antigen (CEA) levels were detected. The nodule diameters and consolidation⁃to⁃tumor ratio (CTR) of CT imaging were measured. The positive rates of 7 TAAbs, TAAbs, and CEA, as well as CTR were compared between the benign group and the malignant group. The receiver operating characteristic curve was used to analyze the efficiency of TAAbs, CEA and CTR in the differentiation of benign and malignant GGN and in the diagnosis of invasion of malignant GGN. Results (1) The positive rates of 4 TAAbs with respect to p53, SOX2, GAGE7, and GBU4⁃5, and the positive rates of TAAbs and CEA in the malignant group were higher than those in the benign group, and the malignant group exhibited larger nodule diameter and CTR. (2) In differentiating benign and malignant GGN, the area under the curve (AUC) of single TAAbs, the number of TAAbs positive antibodies and CEA were less than 0.7; furthermore, AUC of CTR was 0.842, which was greater than that of the number of TAAbs positive antibodies and CEA (P<0.05). AUC of combined detection model (the number of TAAbs positive antibodies+CEA+CTR) was 0.860, which was greater than that of the number of TAAbs positive antibodies and CEA (P<0.05), but there was no statistically significant difference between the combined detection model and CTR (P>0.05). (3) In the diagnosis of malignant GGN invasion, AUC of single TAAbs was less than 0.7, the AUC of the number of TAAbs positive antibodies and CEA were 0.706 and 0.748, respectively. AUC of CTR was 0.879, which was greater than that of the number of TAAbs positive antibodies and CEA (P<0.05). AUC of the combined detection model was 0.922, which was greater than that of CTR, the number of TAAbs positive antibodies and CEA (P<0.05). Conclusion TAAbs combined with CEA and CT imaging indicators has a certain auxiliary value in the diagnosis of GGN, especially in the assessment of malignant GGN invasion, which can improve the diagnostic efficiency and help preoperative risk stratification and clinical decision⁃making.