Sclerosing mesenteritis (SM), also known as mesenteric lipodystrophy, rarely involves the parenchyma of the pancreas. When SM does involve the pancreas, it can mimic pancreatic carcinoma both clinically and radiographically with pain, obstructive jaundice, a mass lesion, and even the appearance of vascular invasion. We report 6 patients with SM involving the pancreas (mean age 43.2 y, 5 female), and review their clinical presentation, radiographic findings, pathology, and outcome. Five of these 6 patients were originally thought to have a primary pancreatic neoplasm. Initial presenting clinical information was available for each patient: all 6 reported abdominal or epigastric pain, 3 reported weight loss, and 2 reported one or more of the following: back pain, fever, abdominal bloating/distention, nausea with/without vomiting, and anorexia. The lesions formed masses with an infiltrative pattern and all had 3 key histologic features: fibrosis, chronic inflammation, and fat necrosis—without a known etiology. The inflammatory infiltrate was composed of a mixture of lymphocytes, plasma cells, and scattered eosinophils. Of the 5 patients with post-treatment clinical information available, 4 had at least a partial response to treatment with steroids, tamoxifen, azathioprine, resection, or a combination of these, and 1 did not respond. A dramatic response to immunosuppressive therapy is illustrated by the case of a 46-year-old woman who presented with the presumptive diagnosis of an unresectable pancreatic cancer. Distinguishing SM from pancreatic carcinoma is crucial to appropriate management, as patients with SM may benefit from immunosuppressive therapy.