The performance of automatic lesion detection is often affected by the intra- and inter-subject feature variations of lesions and normal anatomical structures. In this work, we propose a similarity-guided sparse representation method for image patch labeling, with three aspects of similarity information modeling, to reduce the chance that the best reconstruction of a feature vector does not provide the correct classification. Based on this classification model, we then design a new approach for detecting lesions in positron emission tomography computed tomography (PET-CT) images. The approach works well with simple image features, and the proposed sparse representation model is effectively applied for both detection of all lesions and characterization of lung tumors and abnormal lymph nodes. The experiments show promising performance improvement over the state-of-the-art.