Background Evidence regarding effective nonsurgical management of sciatica remains limited. Purpose To determine a difference in effectiveness between combined pulsed radiofrequency (PRF) and transforaminal epidural steroid injection (TFESI) treatment versus TFESI alone for sciatic pain due to lumbar disk herniation. Materials and Methods This prospective multicenter double-blind randomized clinical trial was conducted between February 2017 and September 2019 in participants with sciatica due to lumbar disk herniation lasting 12 weeks or longer that was not responsive to conservative treatment. Study participants were randomly assigned to undergo one CT-guided treatment with combined PRF and TFESI (n = 174) or TFESI alone (n = 177). The primary outcome was leg pain severity, as assessed with the numeric rating scale (NRS) (range, 0-10) at weeks 1 and 52 after treatment. Secondary outcomes included Roland-Morris Disability Questionnaire (RMDQ) score (range, 0-24) and Oswestry Disability Index (ODI) score (range, 0-100). Outcomes were analyzed according to the intention-to-treat principle via linear regression. Results Mean age of the 351 participants (223 men) was 55 years ± 16 (SD). At baseline, NRS was 8.1 ± 1.1 in the PRF and TFESI group and 7.9 ± 1.1 in the TFESI group. NRS was 3.2 ± 0.2 in the PRF and TFESI group and 5.4 ± 0.2 in the TFESI group (average treatment effect, 2.3; 95% CI: 1.9, 2.8; P < .001) at week 1 and 1.0 ± 0.2 and 3.9 ± 0.2 (average treatment effect, 3.0; 95% CI: 2.4, 3.5; P < .001), respectively, at week 52. At week 52, the average treatment effect was 11.0 (95% CI: 6.4, 15.6; P < .001) for ODI and 2.9 (95% CI: 1.6, 4.3; P < .001) for RMDQ, favoring the combined PRF and TFSEI group. Adverse events were reported in 6% (10 of 167) of participants in the PRF and TFESI group and in 3% (six of 176) of participants in the TFESI group (eight participants did not complete follow-up questionnaires). No severe adverse events occurred. Conclusion In the treatment of sciatica caused by lumbar disk herniation, pulsed radiofrequency combined with transforaminal epidural steroid injection is more effective for pain relief and disability improvement than steroid injection alone. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Jennings in this issue.