Introduction Meniscus degeneration leads to changes in load distribution and loss of cartilage volume, which may cause chronic pain and lead to knee osteoarthritis. For better clinical treatment the physico-chemical hallmarks of meniscus degeneration need further elucidation. In this study, we present a proof of principle for multi- modal physico-chemical assessment. Mechanical properties and chemical composition of the same meniscal tissue sections were assessed via atomic-force microscopy (AFM) micro-indentation and matrix- assisted laser desorption ionization (MALDI) mass spectrometric imaging (MSI), respectively. We hypothesized a correlation between indentation modulus and proteomic composition.