Objectives To develop and test a new multifeature‐based computer‐aided diagnosis (CADx) scheme of lung cancer by fusing quantitative imaging (QI) features and serum biomarkers to improve CADx performance in classifying between malignant and benign pulmonary nodules. Methods First, a dataset involving 173 patients was retrospectively assembled, which includes computed tomography (CT) images and five serum biomarkers extracted from blood samples. Second, a CADx scheme using a four‐step–based semiautomatic segmentation method was applied to segment the targeted lung nodules, and compute 78 QI features from each segmented nodule from CT images. Third, two support vector machine (SVM) classifiers were built using QI features and serum biomarkers, respectively. SVM classifiers were trained and tested using the overall dataset with a Relief feature selection method, a synthetic minority oversampling technique and a leave‐one‐case‐out validation method. Finally, to further improve CADx performance, an information‐fusion method was used to combine the prediction scores generated by two SVM classifiers. Results Areas under receiver operating characteristic curves (AUC) generated by QI feature and serum biomarker‐based SVMs were 0.81 ± 0.03 and 0.69 ± 0.05, respectively. Using an optimal weighted fusion method to combine prediction scores generated by two SVMs, AUC value significantly increased to 0.85 ± 0.03 (P < 0.05). Conclusions This study demonstrates (a) higher CADx performance by using QI features than using the serum biomarkers and (b) feasibility of further improving CADx performance by fusion of QI features and serum biomarkers, which indicates that QI features and serum biomarkers contain the complementary classification information.