The aim of this study is to assess the role of PET/CT in differentiating between mesenteric panniculitis (MP) and co-existing MP and mesenteric tumoural involvement. A total of 33 PET/CT examinations, of 19 oncologic patients (16 men and three women with ages ranging from 48 years to 83 years) with findings of MP on the CT part of the study were retrospectively reviewed. The FDG uptake in mesenteric nodules was recorded. The final diagnosis of malignant mesenteric involvement was based on clinical and imaging follow-up. Based on the FDG uptake in mesenteric nodules, patients were categorized as group A: increased mesenteric uptake (n = 8) and group B: no mesenteric uptake (n = 11). In seven of the eight patients in group A, a co-existing MP and mesenteric tumour involvement was found: one patient had a recurrent cervical carcinoma and the other six patients had lymphoma. In four of these six patients, the positive PET findings disappeared on follow-up PET/CT with complete remission while the CT findings of the MP remained unchanged. In the other two, the PET findings progressed along with clinical deterioration. In the last patient of group A, with rectal carcinoma without evidence of recurrence, the mesenteric FDG uptake was a false positive uptake. In all 11 patients with CT findings of MP and negative PET, no malignant involvement of the mesentery was diagnosed. To conclude, a negative PET has a high diagnostic accuracy in excluding tumoural mesenteric involvement while increased uptake suggests the co-existing of mesenteric deposits, particularly in patients with lymphoma.