The pharmacological anti-inflammatory properties of melanocortin peptides, including α-melanocyte stimulating hormone and pituitary hormone adrenocorticotrophin_1-39, has long been established, however what their main molecular target is still remains unclear; out of the 5 melanocortin receptors cloned so far, there is evidence for a predominant role of MC1R and MC3R, as determined in models of acute inflammation and tissue injury. Furthermore, the patho-physiological impact of this important homeostatic anti-inflammatory system has been poorly studied. Here, we focused on inflammatory arthritis. Arthritis was induced by K/BxN serum transfer into wild type (WT), MC1R mutant (recessive yellow e/e colony) and MC3R null mice (n=12), by injecting 150 µl of serum i.p. on day 0. First signs of arthritis developed from day 2 and were monitored both as clinical score and paw volume (using a water plethysmometer). The results obtained indicated a marked disease exacerbation in MC3R null mice, with a peak at day 6 (P<0.05; two-way ANOVA), whereas no different profile of disease development was displayed by the MC1R mutant and WT mice. This heightened presence of disease in MC3R null mice was confirmed by histological analysis of the paw joints. In contrast to WT animals, a substantial cellular infiltrate was presence with pannus formation and evidence of cartilage/bone erosion in the absence of endogenous MC3R. Interestingly, resolution of arthritis was substantially delayed in MC3R null mice, and this genotype had a much higher disease penetrance when compared to WT and MC1R null mice. The MC3R null phenotype was striking, for instance, 100% of MC3R null mice had developed clear signs of arthritis by day 5, whereas disease penetrance was only 25% in wild type animals and 40% in MC1R nulls (P<0.05, Fisher’s exact test). In conclusion we have demonstrated that when MC3R and not MC1R is void in the mouse system, a host anti-inflammatory response cannot be modulated with consequent exacerbation and prolongation of arthritic joint inflammation. The MC3R could be a novel target for the development of innovative anti-arthritic drugs.