Infective endocarditis (IE) caused by methicillin-resistant Staphylococcus aureus (MRSA) is usually life threatening and difficult to treat. Contezolid is a newly approved oxazolidinone antimicrobial agent showing potent activity against MRSA. We successfully treated a case of refractory IE caused by MRSA with contezolid in a 41-year-old male patient. The patient was admitted due to recurrent fever and chills for more than 10 days. He had chronic renal failure for more than 10 years and under ongoing hemodialysis. The diagnosis of IE was confirmed by echocardiography and positive blood culture of MRSA. Antimicrobial therapy with vancomycin combined with moxifloxacin, and daptomycin combined with cefoperazone-sulbactam failed in the first 27 days. Moreover, the patient had to take oral anticoagulant after removal of tricuspid valve vegetation and tricuspid valve replacement. Contezolid 800 mg was added orally every 12 hours, to replace vancomycin, for its anti-MRSA activity and good safety profile. Temperature normalized after the contezolid add-on treatment for 15 days. No relapse of infection or drug-related adverse reaction was reported at 3-month follow-up since the diagnosis of IE. This successful experience serves as motivation for a well-designed clinical trial to confirm the utility of contezolid in managing IE.