Pylephlebitis or septic thrombophlebitis of the portal vein is a rare entity with a high mortality rate. It is often a complication of intra-abdominal infection most commonly caused by diverticulitis and appendicitis. Diagnosis is often delayed since clinical signs and symptoms are nonspecific. Pylephlebitis should be considered in patients with sepsis due to gut-associated organisms without a clear focus of infection. We describe a patient with metastastatic colon carcinoma treated with chemotherapy and bevacizumab who was diagnosed with pylephlebitis after a duodenal ulcer and responded well to antibiotic treatment.