Colony-stimulating factor-1 (CSF-1) is a key cytokine that has been linked to the development of arthritis in animal models. Its role in neuropathic pain has been studied by several laboratories; however, its potential involvement in arthritic pain has not received attention. Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine which has been implicated in the pathogenesis and progression of RA, as well as the generation of pain. Thus, the objectives of the current study were as follows: 1) to examine the role of CSF-1 in arthritic pain using an acute monoarticular methylated bovine serum albumin (mBSA)-induced arthritis model; 2) to compare the TNF-mediated pain to the CSF-1-induced pain; and 3) to elucidate the mechanisms by which CSF-1 can mediate arthritic pain. Results from this study showed that systemic administration of CSF-1 can induce pain in the mBSA model. Preliminary data showed that early CSF-1-induced pain was not reversed following indomethacin administration, suggesting that CSF-1-mediated pain is cyclooxygenase-independent. Systemic administration of TNF-α could also induce pain in the novel mBSA model. Unlike CSF-1, early TNF-mediated pain was abolished following the administration of indomethacin. This indicated that the TNF-mediated pain is mediated through the production of eicosanoids. Thus, both cytokines were able to induce pain; however, each cytokine mediated arthritic pain via a different pathway. Further insight into the mechanisms by which CSF-1 mediates pain could determine its contribution to arthritic pain and may provide novel therapeutic strategies for joint pain.