Background: Most preventive agents used for transformed migraine (TM)have not been studied specifically for the treatment of this syndrome. Open-label trials have demonstrated the effectiveness of levetiracetam in the treatment of refractory headaches. Objective: The aim of this study was to assess the effectiveness and tolerabilityof levetiracetam in the preventive treatment of refractory TM. Methods: This prospective, open-label, pilot study was conducted at TheNew England Center for Headache, Stamford, Connecticut. We included patients aged ≥ 18 years with refractory TM according to the criteria proposed by Silberstein et al. All participants had failed on at least 1 but not more than 3 preventive drugs. Other preventive drugs were allowed if they had been received at a stable dose for > 30 days. The dosage of the levetiracetam tablets ranged from 1000 to 3000 mg/d in 2 divided doses. The treatment phase lasted 3 months. The primary end point was headache frequency (expressed as the number of headache days per month), and the secondary end point was the frequency of moderate or severe headache (d/mo). Other end points were headache score, Migraine Disability Assessment (MIDAS) Questionnaire score, and Headache Impact Test (HIT-6) score. Statistical analyses were performed in the intent-to-treat (ITT) population (patients who received at least 1 dose of study medication) using data subjected to the last-observation-carried-forward algorithm. We also conducted per-protocol (PP) analyses in patients who completed the study. Results: The ITT population consisted of 36 patients (26 women, 10 men;mean [SD] age, 46.5 [17.4] years). The mean headache frequency at baseline was 24.9 d/mo, and a significant reduction in headache frequency was obtained at l, 2, and 3 months of treatment (19.4, 18.4, and 16.2 d/mo, respectively; all, P < 0.001 Reproduction in whole or part is not permitted. vs baseline). At baseline, the mean number of moderate or severe headache days was 16.8 d/mo compared with 13.2, 11.9, and 9.7 d/mo at 1, 2, and 3 months, respectively ( P=NS, <0.01, and <0.01, respectively). The mean MIDAS score was significantly reduced at 3 months compared with baseline (40.8 vs 62.8 d/mo; P = 0.01). The mean HIT-6 score was 59.4 at 3 months versus 63.4 at baseline ( P < 0.01). In the PP population, the mean (SD) headache frequency was reduced from 26.1 (4.1) d/mo at baseline to 14.3 (4.8) d/mo at the end of the study ( P < 0.001). The mean (SD) headache score was reduced from 51.3 (17.1) at baseline to 34.0 (22.0) at 3 months ( P < 0.016). Conclusion: The results of this study in patients with TM support the role of levetiracetam in the preventive treatment of refractory TM.