Whipple’s disease (WD) is caused byTropheryma whipplei, frequently found in lamina propria’s macrophages in the small intestine. It is a rare and chronic systemic infection, and the principal clinical manifestations are diarrhea, weight loss, abdominal pain, and arthralgia. The diagnosis is difficult mainly because of its rarity and should be considered in patients with arthralgias, diarrhea, abdominal pain, and weight loss after more common conditions have been excluded. The laboratory diagnosis is established by a duodenal biopsy. The treatment involves 14 days of intravenous antibiotics with good penetration in the cerebrospinal fluid (i.e., ceftriaxone) and one-year treatment with oral co-trimoxazole. Early diagnosis and proper treatment are crucial because it improves the prognosis.We report the case of a 58-year-old female with skin hyperpigmentation, loss of appetite and weight (16% of body weight in three months), nausea, upper abdominal pain, and diarrhea. Esophagogastroduodenoscopy and colonoscopy were performed to obtain biopsy samples, which, together with laboratory tests and microbiological studies, led to a diagnosis of Whipple’s disease.