Background For controlling post-thoracotomy pain, thoracic epidural (TE) analgesia is considered a gold standard technique. However, it may be associated with serious complications. Interpleural (IP) analgesia is thought to be a simpler technique. Therefore, the current study aimed to compare the efficacy of simple IP with TE bupivacaine in controlling post-thoracotomy pain in pediatrics. Patients and methods A total of 80 pediatric patients undergoing elective thoracotomy were randomly assigned to either the TE or the IP group. In the TE group, epidural catheter was threaded through the caudal space and the tip was placed at the fourth intercostal space. In the IP group, the surgeon inserted the IP catheter through the IP space under direct vision and directed its tip towards the fourth intercostal space on the paravertebral line. Bupivacaine 1.5 mg/kg in 25% concentration was administered through either TE or IP catheters as intermittent boluses every 6 h, starting from the beginning of skin closure, for 24 h postoperatively. Fentanyl 1 mg/kg intravenous bolus was administered as rescue analgesia to keep the pain score less than 0.4. Hemodynamic parameters and pain scores were recorded at 1, 6, 12, 18, and 24 h. In addition, interleukin-6 was measured at 1, 6, and 24 h beginning from the first injected local anesthetic dose. Total postoperative 24 h fentanyl requirements and time to first postoperative rescue analgesia were recorded. Results CRIES pain score showed no significant difference between the studied groups. Time to first rescue analgesia was significantly shorter in the IP group (2.75 ± 0.93) compared with the TE group (4.17 ± 1.07). Patients of the IP group required higher doses of intravenous fentanyl than did those in the TE group (12.83 ± 3.83 vs. 8.16 ± 3.4μg) (P Conclusion For post-thoracotomy pain in pediatrics, equipotent analgesia can be achieved through TE blockade and the simpler IP technique, but with higher postoperative intravenous fentanyl supplementation to the latter technique.