The destruction of articular cartilage in osteoarthritis involves chondrocyte dysfunction and imbalanced extracellular matrix (ECM) homeostasis.  Pro-inflammatory cytokines such as interleukin-1a (IL-1a) contribute to osteoarthritis pathophysiology, but the effects of IL-1a on chondrocytes within their tissue microenvironment have not been fully evaluated.  To redress this we used label-free quantitative proteomics to analyse the chondrocyte response to IL-1a within a native cartilage ECM.  Mouse femoral heads were cultured with and without IL-1a and both the tissue proteome and proteins released into the media were analysed.  Mass spectrometry identified 728 proteins and 368 proteins in the cartilage proteome and secretome, respectively.  New elements of the chondrocyte response to IL-1a related to cellular stress included markers for protein misfolding (Armet, Creld2 and Hyou1), enzymes involved in glutathione biosynthesis and regeneration (Gstp1, Gsto1 and Gsr) and oxidative stress (Prdx2, Txn, Atox1, Hmox1 and Vnn1).  Other proteins previously not associated with the IL-1a response in cartilage included ECM components (Smoc2, Kera and Crispld1) and cysteine proteases (cathepsin Z and legumain), while chondroadherin and cartilage-derived C-type lectin (Clec3a) were identified as novel products of IL-1a induced cartilage degradation.  This comprehensive view of the cartilage IL-1a response identified candidate biomarkers of cartilage destruction and novel targets for therapeutic intervention in osteoarthritis.