As the number of patients undergoing total joint replacement (TJR) surgery increases, so does the number of revision surgeries. One driver of implant failure and subsequent revision surgery is peri-implant osteolysis, which is driven by inflammation-mediated bone loss. IL-6 is an inflammatory cytokine that is elevated during the peri-operative period. Early elevations in IL-6 levels have been linked to osteolysis development. The current study asked whether there is genetic contribution to the IL-6-related peri-operative inflammatory reaction to TJR surgery. Patients undergoing primary TJR (total hip or total knee) provided pre-operative and post-operative blood samples for measurement of the circulating levels of IL-6 and the soluble IL-6 receptor (sIL-6r), as well as evaluation of allele status of three single nucleotide polymorphisms (SNPs) linked to IL-6 or sIL-6r levels - rs2069845, rs2228145, and rs4537545. Circulating sIL-6r levels were associated with allele status in the rs2228145 SNP. More interestingly, allele status in the rs2069845 SNP was associated with the change in circulating IL-6 levels following TJR surgery. Specifically, patients with the A,A allele had increasing levels of IL-6, while those harboring the G,A allele had decreasing levels of IL-6. While implant survival was not assessed, the critical role of IL-6 in peri-implant osteolysis suggests that the rs2069845 allele may influence orthopedic implant success. rs2069845 polymorphisms may be a useful patient-specific marker of inflammatory response to TJR surgery.