Degenerative osteoarthritis (OA) has been associated with elevated synovial fluid cytokines. It is unclear whether traumatic knee injuries are a trigger to the chemical process that leads to OA. The purpose of this study was to compare the synovial fluid cytokine levels between knees undergoing arthroscopy due to a documented inciting injury and knees undergoing primary arthroplasty due to end-stage OA without a previous inciting injury. Synovial fluid samples were prospectively collected from knees undergoing arthroscopic surgeries due to ligamentous or meniscal knee injuries (knee injury group, n = 16) and primary arthroplasty due to OA (end-stage OA group, n = 14). In the knee injury group, patients had none or minimal OA and at least 30 days from the inciting injury. Exclusion criteria for both groups included inflammatory arthropathy (n = 1) and insufficient fluid for analysis (n = 1). In addition to synovial fluid cytokines, preoperative demographic, clinical, and functional data (Knee Injury and Osteoarthritis Outcome Score [KOOS]) were collected and compared between the groups. The end-stage OA group had higher age (p < 0.0001), body mass index (p = 0.0061), Charlson comorbidity index (<0.0001), and OA classification (p < 0.0001). Preoperative KOOS were similar between the groups. Interleukin-6 (IL-6) and IL-8 were elevated in the end-stage OA group compared with the knee injury group (p = 0.04 and 0.006, respectively). Granulocyte-macrophage colony-stimulating factor, interferon gamma, IL-1β, IL-12p70, IL-2, IL-10, and tumor necrosis factor alpha were not statistically different between the groups. A similar synovial fluid cytokine profile was found between the two groups. The elevation of IL-6 and IL-8 in the end-stage OA group indicates the potential role that these proinflammatory cytokines may have in long-term cartilage damage.