Prostaglandins appear to reduce biofilm formation and chronicization of infections, and stimulate a rapid and effective clearance of infecting micro-organisms. We report a case of recovery from methicillin-susceptible Staphylococcus aureus (MSSA) osteomyelitis after multidisciplinary management with antibiotics, anti-thrombotics and prostaglandin E1 (PGE1) vasodilator, in a patient with tibial plateau fracture repaired with internal fixation devices. A 47-year-old HIV-negative male with chronic ulcer on the proximal third of the left leg was admitted to the Orthopaedic Unit of the Orestano Clinic in Palermo, Italy, for suspected osteomyelitis. A biopsy of the skin ulcer and blood cultures were performed and resulted positive for MSSA. Labelled leukocyte scintigraphy confirmed osteomyelitis. No clinical improvement was observed after combined antibiotic treatment with rifampicin plus trimethoprim-sulfamethoxazole. The patient underwent a 4-day therapeutic cycle: PGE1 (alprostadil 60 mg/day IV) combined with nadroparin calcium plus gentamicin, followed by treatment with aminaftone plus sulodexide plus levofloxacin. At discharge, the patient's painful symptoms had completely resolved and the ulcer had cicatrized; recovery from osteomyelitis was confirmed by scintigraphy. This treatment protocol including PGE1 may result in a significant improvement in quality of life and functional status of patients with a reduction in direct and indirect costs and economic benefit for the National Health Service.