Methicillin-resistant Staphylococcus aureus (MRSA) is an established nosocomial pathogen with frequent multidrug resistance. The immaturity of the immune system along with intravascular lines and empirical antibiotic treatments place hospitalized preterm infants at major risk of MRSA infection.We report a case of MRSA mandibular osteomyelitis complicating a persistent S. aureus bacteremia in a 23-week preterm infant. From the first weeks of life, the infant showed recurrent C-reactive protein (CRP) elevation, associated with S. aureus bacteremia. Antibiotic courses, including vancomycin and linezolid, were performed with transitory normalization of blood parameters. On day 74, the infant suddenly deteriorated and showed a significant increase of both CRP and procalcitonin. Empiric vancomycin and piperacillin-tazobactam treatment was started; nevertheless, she developed a progressive hard swelling of neck and mandible. Radiological evaluation revealed a mandibular osteomyelitis complicated by an abscess, whose culture grew MRSA. Vancomycin was thus changed to teicoplanin and complete clinical and radiological healing was gradually achieved.In the presence of major risk factors, persistent bacteremia and nonspecific symptoms, a localized focus of infection should be suspected. Microbiological diagnosis should always be attempted and antibiotic treatment should be guided by both susceptibility results and clinical response.