Purpose This study was designed to evaluate the efficacy of CT-guided injection of anesthetic and corticosteroid for the treatment of pain in patients with piriformis syndrome unresponsive to conservative treatment. Methods Weenrolled 23 patients with piriformis syndrome, proposing a percutaneous intramuscular injection of methylprednisone-lidocaine. Among them, 13 patients accepted and 10 refused to undergo the procedure; the second group was used as a control group. Clinical evaluation was performed with four maneuvers (Lasegue sign, FAIR test, Beatty and Freiberg maneuver) and a VAS questionnaire before the injection, after 5-7 days, and after 2 months. A telephonic follow-up was conducted to 3, 6, and 12 months. Results Procedural success was achieved in all patients who were treated without any complications. After 2 months, among 13 treated subjects, 2 of 13 patients showed positivity to FAIR test (hip flexion, adduction, and internal rotation), 2 of 13 were positive to Lasegue sign, and the Beatty maneuver was positive in 1 patient. Patients who underwent conservative treatment were positive respectively in 7 of 10 (p = 0.01), 6 of 10 (p = 0.03), and 6 of 10 (p = 0.01). The VAS score showed a difference between patients treated with percutaneous approach and those managed with conservative therapy at the baseline evaluation (p = 0.04), after 2 months (p = 0.02), and 12 months (p = 0.002). We observed a significant reduction in pain for patients treated percutaneously, who were evaluated with the VAS scale at 5-7 days, 2 months, 3, 6, and 12 months (p < 0.001). Conclusions Our findings suggested potential benefit from the percutaneous injection of anesthetics and corticosteroids under CT guidance for the treatment of piriformis syndrome.