The best treatment for Tropheryma whipplei infections is controversial. We report a patient who suffered from T. whipplei aortic native valve endocarditis that relapsed despite surgery and four weeks of intravenous ceftriaxone followed by several months of oral trimethoprim/sulfamethoxazole. Cure was achieved after replacement of the prosthesis with a homograft and 18 months of oral doxycycline-hydroxychloroquine. We discuss the need for a change in treatment guidelines for T. whipplei infections.