Background – Genome-wide association studies identified two single-nucleotide polymorphisms (SNPs), rs204989 and rs204991, that are significantly less prevalent in individuals with Rheumatoid Arthritis (RA). We addressed whether GPSM3 SNPs result in a detectable phenotype explaining their inverse association with RA. Methods – A WVU IRB-approved study (#1304033165) recruited 200 volunteers for blood samples. SNP genotypes were determined using TaqMan probes for rs204989 (GPSM3), rs204991 (GPSM3), rs2812378 (CCL21) and rs6457620 (HLA gene region). 3.5 kb of sequence 5′ to the GPSM3 transcription start site from select volunteers was subcloned into a luciferase reporter vector to assess promoter strength as a function of genotype. THP-1 and NB4 cell lines were transfected with lentivirus expressing shRNA directed toward the GPSM3 transcript to mimic decreased GPSM3 expression as observed in volunteers bearing the minor allele of rs204989. Resultant cell lines were assessed in Transwell migration assays for chemotactic responsiveness. Results – The presence of the SNP rs204989 was seen to reduce GPSM3 expression. Reduced GPSM3 expression in turn was observed to reduce THP-1 and NB4 cell line migration towards relevant chemoattractants. Conclusions – The GPSM3 gene variant rs204989 may protect against RA development by decreasing GPSM3 expression and, thereby, reducing neutrophil and/or monocyte trafficking to the inflammed joint.