Background Thoracic epidural placement (TEP) using the conventional anatomic landmark-based technique is technically challenging, may require multiple attempts, and is associated with a high failure rate (12–40%). We hypothesized that real-time ultrasound guidance would be superior in the “first-pass” success rate of TEP, when compared with the conventional technique. Methods This prospective, randomized, superiority trial was conducted in a University hospital, and recruited 96 patients undergoing elective major abdominal or thoracic surgery and scheduled to receive a TEP for postoperative analgesia. Patients were randomly allocated to receive TEP using either the conventional technique (Gp-Conv, n = 48) or real-time ultrasound guidance (Gp-Usg, n = 48). The success of TEP was defined as eliciting loss of resistance technique and being able to insert the epidural catheter. The primary outcome variable was the “first-pass success rate” meaning the successful TEP at the first needle insertion without redirection or readvancement of the Tuohy needle. The secondary outcomes included the number of skin punctures, number of attempts, the overall success rate, TEP time, and total procedure time. Results The first-pass success rate of TEP was significantly higher (p = 0.002) in Gp-Usg (33/48 (68.8%); 95%CI 55.6 to 81.9) than in Gp-Conv (17/48 (35.4%); 95%CI 21.9 to 49.0). There was no statistically significant difference (p = 0.12) in the overall success rate of TEP between the 2 study groups (Gp-Usg; 48/48 (100%) vs. Gp-Conv; 44/48 (91.7%); 95%CI 83.9 to 99.5). Ultrasound guidance reduced the median number of skin punctures (Gp-Usg; 1 [1, 1] vs Gp-Conv; 2 [1, 2.2], p < 0.001) and attempts at TEP (Gp-Usg; 1 [1, 2] vs Gp-Conv; 3 [1, 7.2], p < 0.001) but the procedure took longer to perform (Gp-Usg; 15.5 [14, 20] min vs Gp-Conv; 10 [7, 14] min, p < 0.001). Conclusions This study indicates that real-time ultrasound guidance is superior to a conventional anatomic landmark-based technique for first-pass success during TEP although it is achieved at the expense of a marginally longer total procedure time. Future research is warranted to evaluate the role of real-time ultrasound guidance for TEP in other groups of patients. Trial registration Thai Clinical Trials Registry; http://www.thaiclinicaltrials.org/; Trial ID: TCTR20200522002, Registration date: 22/05/2020.