Melanocortin peptides display anti-inflammatory effects in models of acute and chronic inflammation via activation of a subgroup of G-protein coupled receptors[1]. To date, five melanocortin receptors (MCR) have been identified, with the MC3R being postulated as one of the receptors involved in modulating inflammation associated with arthritic pathologies[2]. Here, we have used an in vitro model of chondrocyte stimulation to determine the anti-inflammatory effects of melanocortins and to establish their potential as novel therapeutics in osteoarthritis. RT-PCR was used to determine the alteration in mRNA expression of IL-6/IL-8 in the C-20/A4 chondrocyte cell-line[3] following PBS and TNF-α (60pg/ml) treatment. In separate experiments mRNA for MC3R was determined in these cells. Cells were plated at 1×10^6/well in 24-well plates and pre-treated with 1-10μg/ml of the selective MC3R agonist dTrp8-γ-MSH[1] for 30 mins prior to determination of cAMP accumulation by EIA. Cells were pre-treated with 1-10μg/ml of dTrp8-γ-MSH for 30mins prior to stimulation with either PBS or TNF-α (60pg/ml) for 6h. In separate experiments cells were incubated with 3 μg/ml of dTrp8-γ-MSH in the presence of the MC3R antagonist SHU9119 (10μg/ml). Cell-free supernatants were collected and analysed for the cytokines IL-6 and IL-8 by commercially available ELISA. Data is expressed as Mean ± SD of n=5 determinations in triplicate. *P<0.05 vs. appropriate control. C20/A4 cells indicated basal expression of MC3R by RT-PCR, whilst TNF-α treatment resulted in a significant increase in both IL-6 and IL-8 mRNA (*P<0.05) compared to untreated control cells. Receptor functionality was evaluated by stimulating cells with dTrp8-γ-MSH, resulting in a concentration dependent increase in cAMP accumulation. A maximal accumulation of 175.3 ± 19.6 fmol/well at 10 μg/ml (n=5, *P<0.05) increases of ~87% over control (93.3 ± 4.5 pg/ml) was observed. The peptide dTrp8-γ-MSH was then evaluated for its ability to modulate TNF-α stimulated IL-6 and IL-8 release. Stimulation of cells with TNF-α resulted in significant increase in IL-6 (154.3 ± 1.3 pg/ml) and IL-8 (558.9 ± 11.3 pg/ml) compared to control (20.5 ± 3.6 pg/ml and 21.7 ± 2.4 pg/ml for IL-6 and IL-8 resepctively). Pre-treatment of chondrocytes with dTrp8-γ-MSH resulted in a significant reduction in IL-6 (66% *P<0.05, n=5) and IL-8 (74% *P<0.05, n=5); this inhibition was blocked in the presence of the MC3R antagonist SHU9119. Collectively these data have identified functionally active MC3R on C-20/A4 cells and that activation of these cells with dTrp8-γ-MSH inhbitis pro-inflammatory cytokines an effect blocked by the MC3R antagonist SHU9119.