ObjectivePreoperative noninvasive diagnosis of the benign or malignant solitary pulmonary nodule (SPN) is still important and difficult for clinical decisions and treatment. This study aimed to assist in the preoperative diagnosis of benign or malignant SPN using blood biomarkers.MethodsA total of 286 patients were recruited for this study. The serum FR+CTC, TK1, TP, TPS, ALB, Pre-ALB, ProGRP, CYFRA21-1, NSE, CA50, CA199, and CA242 were detected and analyzed.ResultsIn the univariate analysis, age, FR+CTC, TK1, CA50, CA19.9, CA242, ProGRP, NSE, CYFRA21-1, and TPS showed the statistical significance of a correlation with malignant SPNs (P <0.05). The highest performing biomarker is FR+CTC (odd ratio [OR], 4.47; 95% CI: 2.57–7.89;P <0.001). The multivariate analysis identified that age (OR, 2.69; 95% CI: 1.34–5.59,P= 0.006), FR+CTC (OR, 6.26; 95% CI: 3.09–13.37,P<0.001), TK1 (OR, 4.82; 95% CI: 2.4–10.27, P<0.001), and NSE (OR, 2.06; 95% CI: 1.07–4.06,P= 0.033) are independent predictors. A prediction model based on age, FR+CTC, TK1, CA50, CA242, ProGRP, NSE, and TPS was developed and presented as a nomogram, with a sensitivity of 71.1% and a specificity of 81.3%, and the AUC was 0.826 (95% CI: 0.768–0.884).ConclusionsThe novel prediction model based on FR+CTC showed much stronger performance than any single biomarker, and it can assist in predicting benign or malignant SPNs.