This study aimed to elucidate whether CSN1S2 protein of goat's milk was able to inhibit pro-inflammatory cytokine [interleukin (IL)-17 and tumor necrosis factor (TNF)-a], RAGE, and caspase-3 expression in rheumatoid arthritis (RA) rats. A total of 24 Wistar female rats, were randomly assigned into four groups: control group (C), CSN1S2 protein of goat's milk group (CM), CFA-induced RA-rats group (RA), and the RA group treated by CSN1S2 protein of goat's milk (RAM). The severity of erythema and swelling in lower extremities were counted by scoring. IL-17, TNF-a, RAGE, and caspase-3 expression in synovial membranes were analyzed by confocal laser scanning microscopy (CLSM) and western blotting. Erythema and swelling in the RA group was significantly attenuated by goat's milk CSN1S2 (p < 0.05), but did not reach the level in the control group (p < 0.05). The use of CLSM, CSN1S2 protein of goat's milk could decrease the TNF-a, caspase-3, and the number of hyperplasia cells in comparison with the RA group (p < 0.05), to reach the level in the control group (p > 0.05). Western blotting analysis showed that the expression of IL-17, RAGE, TNF-a, and caspase-3 were higher in the RA group compared with the control group. CSN1S2 protein Please cite this article in press as: Bia RR, et al., Goat milk CSN1S2 is able to decrease the severity scoring, tumor necrosis factor-alpha, and advanced glycation end products receptor expression in complete Freund's adjuvant-induced rheumatoid arthritis model of rats, Biomarkers and Genomic Medicine (2015), http://dx.Biomarkers and Genomic Medicine (2015) xx, 1e8 of goat's milk decreased RAGE and TNF-a expression, but increased the IL-17 and caspase-3 expression. In conclusion, CSN1S2 protein of goat's milk decreased erythema, swelling, and inflammation in lower extremities. The CSN1S2 protein of goat's milk also decreased TNF-a and RAGE expression in the synovial membrane of ankle joints. Unfortunately, CSN1S2 protein of goat's milk may induce the production of IL-17. Therefore CSN1S2 protein of goat's milk may provide a nutritional therapy for attenuating the inflammation found in rheumatoid arthritis.