Introduction: Piriformis syndrome is entrapment of the sciatic nerve by the piriformis muscle. Methods: In this article we describe a 56-person randomized, double-blind, controlled study involving physical therapy and incobotulinum toxin A or placebo. Inclusion criteria were 3-SD delay of posterior tibial (PT) or fibular (FN) H-reflexes on flexion, adduction, and internal rotation (FAIR) testing, and normal paraspinal electromyographic findings. Outcome measures included adverse side effects, visual analog scale (VAS) findings, and H-reflex delay on the FAIR test. Results: Mean intervention VAS score decreased significantly more compared with placebo at 2, 4, 6, 8, 10, and 12 weeks post-injection (P < 0.0001). FAIR test scores for PT, but not FN, decreased significantly more compared with placebo at 2, 4, 6, and 8 weeks post-injection (PT: P50.038, 0.003, 0.003, and 0.046). Adverse effects were minimal. VAS slope and PT FAIR test results varied significantly (P < 0.0001). Conclusion: Incobotulinum toxin A chemodenervation may be useful for treating piriformis syndrome as identified by the FAIR test.