Osteoarthritis (OA) is characterized by deterioration of articular cartilage driven by an imbalance of pro- and anti- inflammatory cytokines. To address the cartilage deterioration observed in OA, an autologous protein solution (APS) has been developed which has been shown to inhibit the production of destructive proteases and inflammatory cytokines from chondrocytes and monocytes, respectively. The purpose of this study was to determine the chondroprotective effect of APS on IL-1a– or TNFa-challenged bovine articular cartilage explants. Cartilage explants were cultured in the presence or absence of recombinant inflammatory cytokines, IL-1a and TNFa. Explants under equivalent inflammatory conditions were pretreated with recombinant antagonists IL-1ra, sTNF-RI, or APS to measure their inhibition of matrix degradation. Explants were further evaluated with Safranin-O, Masson’s Trichrome, and Hematoxylin and Eosin histological staining. APS was more effective than recombinant antagonists in preventing cartilage matrix degradation and inhibited any measurable IL-1a-induced collagen release over a 21-day culture period. APS treatment reduced the degree of Safranin-O staining loss when cartilage explants were cultured with IL-1a or TNFa. Micrographs of APS treated cartilage explants showed an increase in observed cellularity and apparent cell division. APS may have the potential to prevent cartilage loss associated with early OA.