Curcumin has been used as an anti-inflammatory agent, however recent studies have shown that it is a combination of three compounds namely; curcumin, Demethoxycurcumin (DMC), Bisdemethoxycurcumin (BDMC). This research evaluates the most effective curcuminoid for treating rheumatoid arthritis (RA) by monitoring changes in the expression levels of 10 inflammatory response genes namely, COL14A1,CXCL12, CYTL1, HSPA6,IFTIM1,IL-6,IL-7, MMP-1,MMP-13 andTNFSF10. The expression profiles of the candidate genes were determined by qRT-PCR analysis using untreated and curcumin, DMC, or BDMC treated Human Fibroblast like Synoviocytes (HFLS-RA) cells. Methotrexate (MTX) was used as a positive control. The level of C-reactive protein (CRP) in the cell culture supernatant was determined using ELISA assays. The untreated HFLS-RA cells exhibited high expression levels of these genes which subsequently was reduced following treatment. Curcumin exhibited increased potency in downregulating the gene expression of COL14A1, CYTL1, IFITM1, IL-7, MMP-1, MMP-13 and TNFSF10 in comparison to the other treatment options. The CRP level decreased on treatment with the curcuminoid mixture,curcumin and DMC, which correlated with the IL-6 transcription profile. The presence of DMC and BDMC were found to limit curcumin’s efficacy as a mixture since curcumin alone was found to be the most effective anti-rheumatic agent.