Candida parapsilosis is an uncommon cause of invasive endocarditis. This pathogen induces severe complications and carries a high mortality rate. We describe a case of C. parapsilosis endocarditis in a 54-year-old man with a history of HIV and Hepatitis C infection who previously underwent prosthetic valve replacement due to bacterial endocarditis. The patient presented with prolonged febrile episodes and fungemia with repeat blood cultures positive for C. parapsilosis. The patient failed multiple regimens of antifungal therapy and the C. parapsilosis isolate progressively acquired resistance to a number of drugs. Due to the multidrug resistant nature of the isolate, replacement of the infected valve was required to resolve his fungemia, and the patient remained asymptomatic for two years. This case is unusual due to the multidrug resistant nature of the isolate requiring both combined medical and surgical intervention. A review of published reports indicates that endocarditis due to C. parapsilosis responds well to a combination of medical and surgical interventions; the latter is particularly suitable for immunocompromised hosts.