It has been proved that Raman spectral intensities could be used to diagnose lung cancer patients. However, the application of Raman spectroscopy in identifying the patients with pulmonary nodules was barely studied. In this study, we revealed that Raman spectra of serum samples from healthy participants and patients with benign and malignant pulmonary nodules were significantly different. A support vector machine (SVM) model was developed for the classification of Raman spectra with wave points, according to ANOVA test results. It got a good performance with a median area under the curve (AUC) of 0.89, when the SVM model was applied in discriminating benign from malignant individuals. Compared with three common clinical models, the SVM model showed a better discriminative ability and added more net benefits to participants, which were also excellent in the small-size nodules. Thus, the Raman spectroscopy could be a less-invasive and low-costly liquid biopsy.© 2023 The Author(s).