To present the clinical and pathological findings in patients presenting with myositis caused by syphilis. The literature is reviewed, and pathophysiologic factors discussed. A 49-year-old Caucasian heterosexual male with a known history of stable human immunodeficiency virus (HIV) and hepatitis C (HCV) co-infection, developed progressive muscle weakness over 10 weeks. He discontinued his medications; however, he had on-going muscle symptoms. A muscle biopsy was performed, consistent with mild myositis. While on prednisone therapy, he developed panuveitis and vertigo. CSF studies were positive for syphilis (Treponema pallidum). He was started on appropriate antibiotic therapy with complete clinical resolution. This patient presented with myositis and panuveitis as a manifestation of acute onset of syphilis. Syphilis is an uncommon cause of myositis. In patients with HIV and/or HCV, the disease itself and side effects of the medications must be considered. As patients with HIV may have co-infections, syphilis must be considered, especially when unresponsive to traditional management.