This study classifies lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) using subregion-based radiomics features extracted from positron emission tomography/computed tomography (PET/CT) images. In this study, the standard 18F-fluorodeoxyglucose (FDG) PET/CT images of 150 patients with lung ADC and 100 patients with SCC were retrospectively collected from the PET Center of the First Affiliated Hospital, College of Medicine, Zhejiang University. First, the 3D feature vector of each tumor voxel (whose basis is PET value, CT value, and CT local dominant orientation) was extracted. Using K-means individual clustering and population clustering, each tumor was divided into 4 subregions that reflect intratumoral regional heterogeneity. Next, based on each subregion, 385 radiomics features were extracted. Clinical features including age, gender, and smoking history were included. Thus, there were a total of 1,543 features extracted from PET/CT images and clinical reports. Statistical tests were then used to eliminate irrelevant and redundant features, and the recursive feature elimination (RFE) algorithm was used to select the best feature subset to classify SCC and ADC. Finally, 7 types of classifiers were tested to achieve the optimized model for the classification: support vector machine (SVM) with linear kernel, SVM with radial basis function kernel (SVM-RBF), random forest, logistic regression, Gaussian process classifier, linear discriminant analysis, and the AdaBoost classifier. Furthermore, 5-fold cross-validation was applied to obtain the sensitivity, specificity, accuracy, and area under the curve (AUC) for performance evaluation. Our model exhibited the best performance with the subregion radiomics features and SVM-RBF classifier, with a 5-fold cross-validation sensitivity, specificity, accuracy, and AUC of 0.8538, 0.8758, 0.8623, and 0.9155, respectively. The interquartile range feature from subregion 2 of CT and the gender feature from the clinical reports are the 2 optimized features that achieved the highest comprehensive score. Our proposed model showed that SCC and ADC could be classified successfully using PET/CT images, which could be a promising tool to assist radiologists or medical physicists during diagnosis. The subregion-based method illustrated that non-small cell lung cancer (NSCLC) depicts intratumoral regional heterogeneity on both CT and PET images. By defining these heterogeneities through a subregion-based method, the diagnostic performance was improved. The 3D feature vector (whose basis is PET value, CT value, and CT local dominant orientation) showed superiority in reflecting NSCLC intratumoral regional heterogeneity.