Purpose: Epidural steroid injection has been prospered in spinal stenosis pain management. Calcitonin is also effective in reliving neuropathic pain in the spinal canal stenosis by arterial dilation, anti-inflammation, anti-edema and beta endorphin level rise. We designed this study to evaluate the effect of mesotherapy with calcitonin compared with epidural steroid injection for pain relief and functional improvement in patients with lumbosacral canal stenosis. Methods: A total of 39 patients with comparable age and sex with signs and symptoms of lumbosacral canal stenosis participated in the two groups; Group A received mesotherapy of 100IU Calcitonin in three repeated injections in the lumbosacral area and group B, single caudal epidural injection of Marcaine 0.5% (4 mL) + 80 mg methyl prednisolone (2mL) + Saline solution 5% (14 mL) under the guide of a fluoroscope. The patients were evaluated before intervention and 4 and 8 weeks after it using visual analog scale (VAS), Oswestry Disability Index (ODI) and Quebec back pain disability scale (QBPD) and Ronald-Morris Disability Questionnaire (RMDQ). Results: A significant improvement in pain and functional disability was observed in both groups based on VAS, ODI and QBPD and RMDQ scales, 4 and 8 weeks after intervention (p <0.05); which was comparable between two groups (P>0.05). Conclusion: Mesotherapy with calcitonin+ marcaine is as effective as caudal epidural steroid injection, so considering its advantages, mesotherapy can be a proper alternative method for managing pain and functional impairment in patients with lumbosacral canal stenosis.