Objective To evaluate the relationships between controlling nutritional status (CONUT), serum expression level of CYFRA21⁃1 and the prognosis of non⁃small cell lung cancer (NSCLC) patients, and to explore the prognostic value of their combination for these patients. Methods The clinicopathological features and follow⁃up data of 168 NSCLC patients who received surgical resection from February 2015 to March 2019 were retrospectively analyzed from Suqian Hospital. The optimal cut⁃off point of serum CYFRA21⁃1 expression for the prediction of overall survival (OS) rate was determined by the receiver operation characteristics curve (ROC curve). Kaplan⁃Meier curve and Cox multivariate regression analysis were used to evaluate the prognostic value of CONUT score and serum CYFRA21⁃1 expression for NSCLC patients. Results All patients were divided into high expression (≥4.05 ng/ml, n=99) and low expression group (<4.05 ng/ml, n=69) based on the cut⁃off value of serum expression level of CYFRA21⁃1. The area under curve (AUC) value of serum CYFRA21⁃1 expression for predicting the OS of NSCLC patients was 0.661 (95%CI=0.553-0.770), the sensitivity and specificity was 78.1% and 58.9%, respectively. Kaplan⁃Meier curves showed that the 3⁃year OS of patients with high and low CYFRA21⁃1 expression was 78.7% and 90.5%, with a significantly statistical difference ( χ２=5.966, P=0.015). High expression of CYFRA21⁃1 was an indicator of poor survival in NSCLC patients. Moreover, high CONUT was associated with poor prognosis of NSCLC patients. The 3⁃year OS of patients with CONUT <2 and CONUT≥2 points were 88.4% and 76.6%, respectively(χ２= 7.526, P=0.006). Compared with other patients, those with CONUT≥ 2 points and high CYFRA21⁃1 expression had the poorest prognosis. The results of the univariate and multivariate Cox analysis demonstrated that T stage (HR=2.382, 95%CI= 1.141-4.969, P=0.021), lymph node metastasis (HR=2.451, 95%CI=1.206-4.982, P=0.013), CONUT (HR=2.636, 95%CI=1.301-5.344, P=0.007) and serum CYFRA21⁃1 expression (HR=2.481, 95%CI=1.071-5.748, P=0.034) were independent prognostic factors for NSCLC patients. Based on the above these factors, a nomogram model for prognostic prediction of NSCLC patients was constructed, and the C⁃index of the model was 0.768 (95%CI=0.678-0.859). Conclusion Preoperative CONUT and serum expression level of CYFRA21⁃1 were independent predictors of poor OS in NSCLC patients, and their combination analysis might provide useful information for prognostic assessment and individualized treatment of NSCLC patients