A 47-year-old dog breeder had suffered from unclassified polyarthritis for four years. During immunomodulatory therapy of an assumed seronegative chronic polyarthritis with Leflunomid and Adalimumab he developed severe systemic inflammatory disease with high fever, weight loss, and severe arthralgia. Fever and arthralgias temporarily improved under antibiotic therapy, although a causative organism had not been found. The clinical picture led to the differential diagnosis of Whipple's disease, but PAS-positive macrophages were not detected in duodenal biopsies. The diagnosis was finally based on a positive PCR result for Tropheryma whipplii, typical clinical symptoms and a complete response on adequate antibiotic long-term treatment with cotrimoxazol. The diagnosis of Whipple's disease was possibly masked by the initial antibiotic therapies. Therapies with immunomodulators, TNF-inhibitors, and corticosteroids may transform an infection with Tropheryma whipplii, normally in a subacute stage, into a septic, life-threatening disease.