BACKGROUND: Cardiac manifestations of Whipple disease are rarely diagnosed before death. OBJECTIVE: To describe four patients with endocarditis caused by Tropheryma whippelii who did not have overt gastrointestinal disease. DESIGN: Case series. SETTING: Five hospitals in eastern Switzerland. PATIENTS: Three men and one woman undergoing replacement of insufficient heart valves. MEASUREMENTS: Histologic characteristics of heart valves and intestinal biopsy; broad-range and specific polymerase chain reaction for T. whippelii. RESULTS: Tropheryma whippelii was found in the heart valves (three aortic valves and one mitral valve) of four patients with culture-negative endocarditis necessitating valve replacement. All patients had arthralgia for different lengths of time. Only one patient had mild gastrointestinal symptoms. Histologic characteristics of intestinal mucosa were normal in all patients, and polymerase chain reaction on intestinal biopsy was positive for T. whippelii in only one patient, who did not have diarrhea. In all patients, arthralgia resolved promptly after institution of antibiotic therapy. Disease did not recur in any patient after prolonged antibiotic therapy with cotrimoxazole. CONCLUSION: In patients with culture-negative endocarditis, the absence of clinical, microscopic, or microbiological evidence of gastrointestinal disease did not rule out T. whippelii.