Background: Long-term remission and total clearance in Psoriasis can only be achieved in a few patients. Aim: To compare the efficacy and safety of intradermal Botulinum toxin (BTX) in the treatment of plaque psoriasis. Subjects and methods: A comparative study conducted in thirty-five patients with chronic plaque psoriasis was treated by split-body therapy. The patients were either treated with intradermal BTX or with intralesional 5-fluorouracil (5-FU) to each of 2 bilaterally symmetrical psoriatic plaque lesions. The outcomes were assessed using the following criteria: the sum of erythema, scaling, and induration scores and the clearing percentage of the target plaque lesion assessed by 2 blinded observers. Results: At the end of the study, the response rate was 85% on the BTX treatment side and 90% on the 5-FU side. There was no significant difference between both sides regarding a clinical response or side effects. The recurrence rate was 15% on both sides. Conclusions: Botulinum toxin was a novel, safe, single injection, and effective therapy for plaque-type psoriasis. More studies are required to further prove the efficacy of BTX in the treatment of plaque psoriasis.