Activation of toll-like receptors (TLR) in articular chondrocytes has been reported to increase the catabolic compartment, leading to matrix degradation, while the main consequence of TLR activation in monocytic cells is the expression and secretion of components of the innate immune response, particularly that of inflammatory cytokines. The objective of the work reported here was to obtain a more complete picture of the response repertoire of articular chondrocytes to TLR activation. Mass spectrometry was used to analyse the secretome of stimulated and unstimulated cells. Characterization of TLR expression in rat articular chondrocytes by RT/PCR indicated that TLR4 was the major receptor form. Exposure of these cells to lipopolysaccharide (LPS), the well-characterized TLR4 ligand, induced production not only of the matrix metalloproteinases MMP3 and 13, but also of components traditionally associated with the innate immune response, such as the complement components C1r, C3 and complement factor B, long pentraxin-3 and osteoglycin. Neither TNF-alpha nor IL-1 was detectable in culture media following exposure to LPS. One of the most prominently-induced proteins was the chitinase-like protein, Chi3L1, linking its expression to the innate immune response repertoire of articular chondrocytes. In intact femoral heads, LPS induced expression of Chi3L1 in chondrocytes close to the articular surface, suggesting that only these cells mount a stress response to LPS. Thus articular chondrocytes have a capacity to respond to TLR activation, which results in the expression of matrix metalloproteases as well as subsets of components of the innate immune response without significant increases in the production of inflammatory cytokines. This could influence the erosive processes leading to cartilage degeneration as well as the repair of damaged matrix.