Background: This study evaluated the efficacy of focal intramuscular injection of botulinum (BoNT) toxin type A in comparison with oral tizanidine (TZD) in treatment of post-stroke upper limb spasticity.Methods: This was a double-blinded randomized clinical trial that recruited 68 patients with post-stroke upper limb spasticity. Thirty-four patients received BoNT (Dysport(®)) injections in affected muscles of upper limb at the baseline and week 12. Thirty-four patients were treated with tizanidine (Sirdalude) by gradual increase in dosage of 2mg/week to reach maximum 24mg at week 12. Modified Ashworth Scale (MAS) and Action Research Arm Test (ARAT) were evaluated at the baseline, week 12 and week 24 for all the participants.Results: The mean score of MAS reduced from 3.32 and 3.13 at baseline to 1.79 and 1.56 at week 24 on elbow and wrist joints, respectively (P < 0.01). However, there were only reductions from 2.79 and 2.77 to 2.32 and 2.31 (P < 0.001) in TZD group. ARAT increased from 1.79 to 10.97 (P < 0.001) in BoNT group. ARAT increased from 11.08 to 11.35 in TZD group (P = 0.026).Conclusion: BoNT injection was safe and effective in reducing post-stroke upper extremity spasticity in comparison with TZD.