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BACKGROUND It is a clinical problem to identify histological component in enlarged cervical lymph nodes, particularly in differentiation between lymph node metastasis and lymphoma involvement. PURPOSE To construct two kinds of deep learning (DL) based computer-aided diagnosis (CAD) systems including DL-convolutional neural networks (DL-CNN) and DL-machine learning for pathological diagnosis of cervical lymph nodes by PET/CT images. METHODS We collected CT, PET, and PET/CT images series from 165 patients with enlarged cervical lymph nodes receiving examinations from January 2014 to June 2018. Six CNNs pretrained on ImageNet as DL architectures were used for two kinds of DL-based CAD models, including DL-CNN and DL-machine learning models. The DL-CNN models were constructed via transfer learning for classification of lymphomatous and metastatic lymph nodes. The DL-machine learning models were developed by DL-based features extractors and SVM classifier. As for DL-SVM models, we also evaluate the effect of handcrafted radiomics features in combination of DL-based features. RESULTS The DL-CNN model with ResNet50 architecture on PET/CT images had the best diagnostic performance among all six algorithms with an area under the receiver operating characteristic curve (AUC) of 0.845 and accuracy of 78.13% in the testing cohort. The DL-SVM model on ResNet50 extractor showed great performance for the testing cohort with an AUC of 0.901, accuracy of 86.96%, sensitivity of 76.09%, and specificity of 94.20%. The combination of DL-based and handcrafted features yielded the improvement of diagnostic performance. CONCLUSIONS Our DL-based CAD systems on PET/CT images were developed for classifying metastatic and lymphomatous involvement with favorable diagnostic performance in enlarged cervical lymph nodes. The further clinical practice of our systems may improve quality of the following therapeutic interventions and optimize patients' outcomes. This article is protected by copyright. All rights reserved.