Osteoarthritis (OA) is a multifactorial pathology which comprises a wide range of distinct phenotypes. The characterization of the different molecular profiles associated to each phenotype can improve the classification of OA for a better personalized medicine. Within the metabolic syndrome phenotype, OA can co-exist with type 2 diabetes (TD2) disease. This study was undertaken to investigate lipidomic and proteomic differences between human OA and OA/TD2 cartilage through a multimodal mass spectrometry approach.