INTRODUCTION: Whipple's disease is a rare systemic infectious disorder. It may present with a wide range of clinical manifestations and therefore its diagnosis may be challenging. CASE REPORT: We report a 45-year-old man who presented with acute encephalitis related to Whipple's disease. Despite the negativity of the polymerase chain reaction (PCR) test in cerebrospinal fluid, diagnosis was obtained by histopathology, PCR tests and immunohistochemistry in multiple samples. The outcome with antibiotherapy was considered as "spectacular". CONCLUSION: Whipple's disease is a rare cause of encephalitis. Its diagnosis needs the confrontation of histology and PCR tests in multiple samples. The outcome with an adapted antibiotherapy may be very successful.