Piriformis syndrome (PS), first described by Yeoman in 1928, is a general term referring to low back pain, sciatica, and instability. PS has a 6% incidence rate worldwide. In this study, we aim to retrospectively evaluate the effectiveness of computed tomography (CT)-guided percutaneous infiltration in a series of consecutive PS patients who have symptoms that are refractory to conservative therapies. An institutional database search identified 20 such consecutive patients who underwent infiltration with a mixture of long-acting corticosteroid and local anesthetic. Preoperational evaluation included physical examination and magnetic resonance imaging. The correct position of the 22-gauge spinal needle was verified with CT scan after contrast medium injection. Pain measured before the procedure and at 1 wk and 1, 6, and 12 mo after the procedure was compared by means of a numeric visual scale (NVS) questionnaire. The mean pain score before CT-guided percutaneous infiltration was 8.95 ± 1.432 NVS units. This score was reduced to a mean value of 0.85 ± 0.933 units at 1 wk, 0.90 ± 0.852 at 1 mo, 1.10 ± 1.165 at 6 mo, and 1.20 ± 1.399 at 12 mo follow-up (p < 0.001). Two patients of 20 (10%) underwent a second infiltration that was performed at 7 and 10 d after the first, respectively. No complications were observed. CT-guided infiltration seems to be a feasible, efficacious, and safe approach for pain reduction and mobility improvement in patients with symptomatic PS.