Interferon-beta (IFN-beta) is a type I interferon used in the management of multiple sclerosis. Therapy with IFN-beta has rarely been associated with the development of autoimmune disorders. We present the cases of two female patients diagnosed with relapsing-remitting multiple sclerosis (RRMS) who developed inflammatory musculoskeletal manifestations, following IFN-beta therapy. The first patient developed a monoarthritis 2 weeks after initiation of IFN-beta, which persisted during the 14 months of therapy and resolved with discontinuation of the medication. The second patient developed both autoimmune thyroid disease and a refractory pre-patellar bursitis after 50 months of IFN-beta therapy. Our literature review revealed an additional six cases of onset of inflammatory arthritis in MS patients receiving IFN-beta. We review these reports with comparison to our two cases. The role of IFN-beta in inflammatory musculoskeletal disease is unclear. The potential autoimmune complications of this therapeutic agent should be comprehended when monitoring patients receiving such treatment.