Objectives: To investigate the clinical value of contrast-enhanced CT combined with PET/CT in the differential diagnosis of mediastinal lymph node metastasis (MLNM) of non-small-cell lung cancer (NSCLC). Methods: A total of 120 patients with NSCLC combined with mediastinal lymphadenopathy hospitalized in our hospital were selected. All the patients received radical resection of lung cancer and mediastinal lymphadenectomy. After pathological diagnosis, they were divided into MLNM group (malignant group, undergoing contrast-enhanced CT) and non-MLNM group (benign group, receiving contrast-enhanced CT combined with PET-CT). The results were judged by two senior radiologists independently. The results of different scanning methods and postoperative pathology were compared using the t test, chi(2) test and Pearson correlation coefficient test. Results: Compared with the pathological results, contrast-enhanced CT diagnosed 31 cases, with a coincidence rate of 62%, and contrast-enhanced CT combined with PET-CT diagnosed 42 cases, with a coincidence rate of 84%, presenting a statistically significant difference (P = 0.02). Among the 120 patients with lung cancer, pathological examination confirmed MLNM in 50 patients and benign enlargement in 70 patients, contrast-enhanced CT alone detected metastasis in 40 patients and benign enlargement in 80 patients, and contrast-enhanced CT combined with PET-CT detected metastasis in 47 patients and benign enlargement in 73 patients. The sensitivity and accuracy of the latter were significantly higher than those of the former (sensitivity, P = 0.01; accuracy, P = 0.01). With the increase in the malignancy of lymph nodes, the degree of CT enhancement, the concentration of radioactive substances and SUV value increased, showing positive correlations. Conclusion: Contrast-enhanced CT combined with PET/CT in the diagnosis of MLNM of NSCLC presents higher coincidence rate, sensitivity and accuracy. With the increase in tumor malignancy, the enhancement degree and radioactive substance concentration increase. The two methods are synergistic and complementary in diagnosing MLNM.