Large cardiac vegetation carries a poor prognosis and high mortality risk, especially if associated with methicillin-resistant Staphylococcus aureus (MRSA) infection. We share our experience of a rare and complicated large cardiac vegetation which had a favourable outcome with combination antibiotic treatment alone. A 35-year-old HIV-negative, HCV-positive male patient with a previous history of methicillin-susceptible S. aureus endocarditis showed MRSA mitral valve endocarditis with large vegetation, complicated by embolic stroke. The strain was soon identified by PCR but only after culture did the patient receive efficacious antibiotics. A combination of daptomycin plus trimethoprim/sulfamethoxazole (TMP/SMX) was administered for six weeks, followed by a high dosage of TMP/SMX for a further six weeks. Effectiveness of the treatment was demonstrated by the patient's clinical improvement and instrumental evidence of cardiac mitral vegetation clearance. Innovative antibiotic strategies in patient management are needed to fight Staphylococcus aureus endocarditis because strains show varying antimicrobial susceptibility patterns in different geographic areas. Timely initiation of targeted antimicrobial therapy remains a crucial step to reduce morbidity and mortality but culture is crucial for appropriate fine-tuning of antibiotic therapy.