Background: Chest surgery is associated with significant pain, and potent opioid medications are the primary medications used for pain relief. Opioid-free anaesthesia (OFA) combined with regional anaesthesia is promoted as an alternative in patients with an opioid contraindication. Methods: Objective: To assess the efficacy of OFA combined with a paravertebral block in pain treatment during video-assisted thoracic surgery. Design: A randomized, open-label study. Setting: A single university hospital between December 2015 and March 2018. Participants: Sixty-six patients scheduled for elective video-assisted thoracic surgery were randomized into two groups. Of these, 16 were subsequently excluded from the analysis. Interventions: OFA combined with a paravertebral block with 0.5% bupivacaine in the OFA group; typical general anaesthesia with opioids in the control group. Main outcome measures: Intraoperative nociceptive intensity measured with a skin conductance algesimeter (SCA) and traditional intraoperative monitoring. Results: Higher mean blood pressure was observed in the control group before induction and during intubation (p = 0.0189 and p = 0.0095). During chest opening and pleural drainage, higher SCA indications were obtained in the control group (p = 0.0036 and p = 0.0253), while in the OFA group, the SCA values were higher during intubation (p = 0.0325). SCA during surgery showed more stable values in the OFA group. Pearson analysis revealed a positive correlation between the SCA indications and mean blood pressure in both groups. Conclusions: OFA combined with a paravertebral block provides effective nociception control during video-assisted thoracic surgery and can be an alternative for general anaesthesia with opioids. OFA provides a stable nociception response during general anaesthesia, as measured by SCA.