Although Whipple disease was described over a century ago, it remains challenging to recognize. To better understand the presentation of Whipple disease, we undertook a clinicopathologic study of our experience since implementation of the Whipple immunohistochemical stain. Twenty-three biopsy specimens from 15 patients were identified, and an association with immunomodulatory conditions was noted. Whipple disease involved the small intestine (19), brain (2), breast (1), and retroperitoneum (1). Whipple disease was suspected by 3 clinicians and by the majority of pathologists (9). Alternative clinical impressions included lymphoma, celiac disease, Crohn vasculitis, sepsis, an inflammatory process, liposarcoma, rheumatoid arthritis, seizure disorder, cerebrovascular accident, xanthoma, and central nervous system neoplasm. The nonspecific nature of the disease presentation likely contributed to the extended period between onset of symptoms and a definitive diagnosis, which ranged from at least 1 year to over 10 years. One patient died of unknown causes, and both patients with detailed follow-up had clinically persistent disease. We also describe Whipple disease with therapy effects, including partial and complete histologic treatment effects. Awareness of the unusual clinicopathologic presentations of Whipple disease is essential for timely diagnosis of this potentially lethal disease.