Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid which is present in high concentration in fish oil. Adjuvant-induced arthritis is an animal model of cachexia that induces muscle wasting by increasing the ubiquitin-proteasome pathway. The aim of this work was to elucidate whether the effect of EPA on arthritis-induced muscle wasting is mediated by changes on muscle proteolysis, regeneration and inflammation. For this purpose, arthritis was induced in male Wistar rats by an intradermal injection of Freund’s adjuvant. Three days after the injection, control and arthritis rats were divided in two experimental groups. One group was daily gavaged with EPA (1g/kg bw) and the other was gavaged with coconut oil (1g/kg bw). Rats were humanly killed after 12 days of treatment. EPA administration to arthritic rats ameliorated arthritis score and hindpaw swelling (P<0.01). Arthritis decreased skeletal muscle weight (P<0.01), whereas EPA administration reduced this effect (P<0.05). EPA prevented arthritis-induced increase of TNF-alpha gene expression both in liver and in gastrocnemius muscle (P<0.01). Arthritis increased the atrogenes MAFbx and MuRF-1 mRNA in gastrocnemius, and this effect was prevented by EPA (P<0.01). Both EPA and arthritis increased differentiation marker myogenin mRNA and protein (P<0.01). Muscular proliferating cell nuclear antigen (PCNA) mRNA and protein were also increased in arthritic and EPA treated rats (P<0.01). These data suggest that EPA exerts an antiinflammatory effect on adjuvant-induced arthritis, and it attenuates muscle wasting by inhibiting proteolysis and stimulating muscle regeneration.