Background: Whether erector spinae plane (ESP) block can replace thoracic paravertebral block (TPVB) remains unknown. This study aimed to determine the efficacy and safety of ultrasound-guided ESP block compared with TPVB for postoperative analgesia after video-assisted thoracoscopic lobectomy under general anesthesia. Methods: This prospective randomized controlled trial divided patients into a control group, a TPVB group (0.3 mL/kg, 0.5% ropivacaine), and an ESP group (0.5 mL/kg, 0.5% ropivacaine). Dermatomes with loss of pinprick sensation, heart rate, and mean arterial pressure were recorded during 30 min after block administration. Visual analog scale (VAS) scores, total analgesic dose, and complications after surgery were recorded. Results: No obvious hemodynamic fluctuations occurred in the TPVB and ESP groups within 30 min after block administration. The segmental dermatomes with loss of pinprick sensation 30 min after regional block were 4.5 (1.1) dermatomes (T3–T7) in the TPVB group and 5.4 (1.2) dermatomes (T2–T8) in the ESP group. At 1 and 6 h after operation, VAS scores were lower in the TPVB group than in the control group (rest: 1h, P<0.001, 6h, P=0.004; cough: 1h, P<0.001, 6h, P<0.001), but at 18, 24, and 48 h, there was no significant difference (rest: 18h, P=0.18, 24h, P>0.99, 48h, P> 0.99; cough: 8h, P>0.99, 24h, P>0.99, 48h, P>0.99). VAS scores were similar in the TPVB and ESP groups at 1 h postoperatively (rest: P>0.99, cough: P>0.99), but were lower in the ESP group at 6, 18, 24, and 48 h (rest: 6h, P=0.018, 18h, P<0.001, 24h, P< 0.001, 48h, P<0.001; cough: 6h, P=0.004, 18h, P<0.001, 24h, P=0.004, 48h, P= 0.003). The doses of postoperative patient-controlled analgesia and rescue analgesia were lower in the TPVB and ESP groups than in the control group and were lower in the ESP group than in the TPVB group No block-related complications occurred. Conclusions: Single ESP block provided superior postoperative analgesia than TPVB, without causing any adverse effect.Trial registration: The study was approved by the ethics committee of Beijing Chaoyang Hospital (2017-ke-81). The trial was registered retrospectively at the Clinical Trial Registry of China (ChiCTR-INR-17011499) on May 26, 2017.