We have performed cDNA sequencing and homology analyses to elucidate the complete amino acid composition for a superficial zone protein (SZP) from human and bovine cartilage which has previously been shown to be a proteoglycan specifically synthesized by chondrocytes located at the surface of bovine articular cartilage and also some synovial lining cells. The results of this study indicate that cartilage SZP is homologous with a glycoprotein first described as the precursor protein of a megakaryocyte stimulating factor (MSF). Sequence comparisons and analyses indicate that (i) the amino acid composition of SZP is highly conserved between bovine and human species, (ii) SZP contains structural motifs at the N- and C-termini which are similar to those found in vitronectin and which may impart cell-proliferative and matrix-binding properties to the molecule, and (iii) SZP contains large and small mucin-like repeat domains composed of the sequences KEPAPTTT/P (76–78 repeats) and XXTTTX (6–8 repeats), respectively, which occur within a large central region of ∼940 amino acids. The mucin-like domains are likely to be substituted with O-linked oligosaccharides which would impart lubricating properties to SZP which in part accumulates at the articular cartilage–synovial fluid interface. Additionally, we have shown that interleukin-1 inhibits the biosynthesis of chondrocyte SZP, while TGF-β and IGF-1 increase its biosynthesis, and that in pathological (osteoarthritic) human articular cartilage SZP mRNA can be expressed as an alternatively spliced variant lacking exons 4 and 5 which encode a potential heparin binding domain. The occurrence of different SZP alternative splice variants and the differential expression of SZP in the presence of cytokines and growth factors suggest that SZP may play an important cytoprotective role by preventing cellular adhesion to the articular cartilage surface in normal cartilage metabolism. Modifications to the structure of SZP, coupled with inhibition of SZP synthesis during inflammation, may account for the attachment and invasion of pannus observed in inflammatory joint diseases.