Background: Mesenteric panniculitis is a rare condition with no standard therapy. Aim: To assess the safety and efficacy of thalidomide for the treatment of patients with symptomatic mesenteric panniculitis using a newly established clinical disease activity index (Mesenteric Panniculitis Subjective Assessment Score). Methods: In an open-label pilot study, five patients with symptomatic mesenteric panniculitis received oral thalidomide, 200 mg nightly, for 12 weeks. The primary end-point was a reduction in the Mesenteric Panniculitis Subjective Assessment Score by 20% at 12 weeks or complete remission (absence of symptoms). Results: Four (80%) of the five patients responded. The median Mesenteric Panniculitis Subjective Assessment Score at baseline was 39 and at week 12 was 25 (average decrease of 44%). One patient achieved complete remission by week 4, which was sustained. At 12 weeks, three (75%) patients experienced a global response, five (100%) patients had a 20% (range, 29-98%) decrease in erythrocyte sedimentation rate and three (75%) patients had a 20% (range, 61-93%) decrease in C-reactive protein. Abdomino-pelvic computed tomography scans were unchanged in all five patients. There were no serious adverse events. Conclusions: Thalidomide is safe, well tolerated and efficacious in the treatment of some patients with symptomatic mesenteric panniculitis. Further study is indicated.