Objective Pro-inflammatory mediators such as prostaglandin E-2 (PGE) play major roles in the pathogenesis of osteoarthritis (OA). Although current pharmacologic treatments reduce inflammation, their prolonged use is associated with deleterious side effects prompting the search for safer and effective alternative strategies. The present study evaluated whether chondrocyte production of PGE can be suppressed by the combination of avocado/soybean unsaponifiables (ASU) and α-lipoic acid (LA). Design Chondrocytes from articular cartilage of equine joints were incubated for 24 hours with: (1) control media, (2) ASU, (3) LA, or (4) ASU + LA combination. Cells were activated with lipopolysaccharide (LPS), interleukin 1β (IL-1β) or hydrogen peroxide (HO) for 24 hours and supernatants were immunoassayed for PGE. Nuclear factor-kappa B (NF-κB) analyses were performed by immunocytochemistry and Western blot following 1 hour of activation with IL-1β. Results LPS, IL-1β, or HO significantly increased PGE production. ASU or LA alone suppressed PGE production in LPS and IL-1β activated cells. Only LA alone at 2.5 µg/mL was inhibitory in HO-activated chondrocytes. ASU + LA inhibited more than either agent alone in all activated cells. ASU + LA also inhibited the IL-1β induced nuclear translocation of NF-κB. Conclusions The present study provides evidence that chondrocyte PGE production can be inhibited by the combination of ASU + LA more effectively than either ASU or LA alone. Inhibition of PGE production is associated with the suppression of NF-κB translocation. The potent inhibitory effect of ASU + LA on PGE production could offer a potential advantage for a combination anti-inflammatory/antioxidant approach in the management of OA.