Background <p>Various analgesic techniques have been applied, the pain after video assisted thoracic surgery (VATS) is still challenging for anesthesiologists. Paracetamol provide analgesic efficacy in many surgeries. However, clinical evidence in the lung surgery with regional block remain limited. This monocentric double-blind randomized controlled trial investigates the efficacy of paracetamol after VATS with regional block.</p> Methods <p>A total of 90 patients were randomized to receive paracetamol (1&#xa0;g) or normal saline. Erector Spinae Plane Block and Intercostal Nerve block were applied during the surgery. The Visual Analogue Scales (VAS) pain score was measured in the PACU as well as 6, 12, 24, and 48&#xa0;h postoperatively. And the total dose of rescue analgesics administered to patients in morphine milligram equivalents (MME), satisfaction score, length of hospital stays, and incidence of nausea and vomiting were also recorded.</p> Results <p>The VAS pain score at each time point, the primary endpoint, did not differ between the groups (3.09 ± 2.14 vs. 2.53 ± 1.67, <i>p</i> = 0.174 at PACU; 4.56 ± 2.80 vs. 4.06 ± 2.46, <i>p</i> = 0.368 at 6&#xa0;h; 3.07 ± 1.98 vs. 3.44 ± 2.48, <i>p</i> = 0.427 at 12&#xa0;h; 2.10 ± 2.00 vs. 2.49 ± 2.07, <i>p</i> = 0.368 at 24&#xa0;h; and 1.93 ± 1.76 vs. 2.39 ± 1.97, <i>p</i> = 0.251 at 48&#xa0;h postoperatively). Satisfaction scores (4.37 ± 0.76 vs. 4.14 ± 0.88, <i>p</i> = 0.201), nausea (35.6% vs. 37.8%, <i>p</i> = 0.827), hypotension (2.2% vs. 0.0%, <i>p</i> = 0.317), and bradycardia (6.7% vs. 2.2%, <i>p</i> = 0.309) were also reported at similar rates.</p> Conclusions <p>The analgesic efficacy of one gram of paracetamol with ESPB and ICNB after VATS was not proven. Thus, caution should be exercised when prescribing paracetamol for pain control during VATS.</p> Trial registration <p>this trial was registered on Clinical Research Information Service (CRIS), Republic of Korea (KCT0008710). Registration date: 17/08/2023.</p>