Hylan G-F 20 (Synvisc-One) is a hyaluronic acid derivative used for viscosupplementation of synovial fluid in osteoarthritic joints. Injection of hylan G-F 20 is Federal Drug Administration approved for use in knee osteoarthritis and is generally well tolerated with few reported adverse effects, the most common being local pain or swelling. We present the case of a 72-year-old man with bilateral, diffuse, joint pain and swelling with elevated inflammatory markers suggestive of a systemic inflammatory polyarthropathy that developed acutely 2 days after lumbar zygapophyseal joint injection with hylan G-F 20. Systemic effects after hylan G-F 20 injection have not been well documented, and this is the first reported case of systemic inflammatory polyarthritis after injection, to our knowledge. Further research is needed to better establish the safety and efficacy of lumbar zygapophyseal joint injections with hylan G-F 20.