INTRODUCTION: Concerns about opioid-related adverse effects have increased interest in opioid-free anaesthesia, but the benefits compared with opioid-inclusive techniques, especially in the presence of regional anaesthesia, remain uncertain. METHODS: We undertook a systematic review with a network meta-analysis of randomised controlled trials comparing six strategies in adults: opioid-free anaesthesia and opioid-inclusive anaesthesia using remifentanil alone or other opioids, each with or without regional anaesthesia. Primary outcome was postoperative pain. Secondary outcomes were: postoperative opioid use; post-anaesthesia care unit discharge time; hospital duration of stay; and incidence of complications. RESULTS: We included 885 trials from 59 countries. Techniques incorporating regional anaesthesia consistently ranked highest for postoperative pain. Regional anaesthesia combined with an opioid-free intra-operative strategy achieved some of the highest surface under the cumulative ranking curve values for pain at 2 h, 12 h and 48 h (93%, 85% and 75%, all low certainty). When regional anaesthesia was used, differences between opioid-free and opioid-inclusive techniques were minimal (moderate certainty). For opioid consumption, regional anaesthesia with an opioid-free strategy ranked best at 2 h (moderate certainty), 12 h (low certainty) and 48 h (low certainty), with surface under the cumulative ranking curve values > 98%. Techniques without regional anaesthesia were associated with higher pain scores and greater opioid requirements. Opioid-free approaches, especially when combined with regional techniques, were associated with lower rates of postoperative nausea and vomiting. DISCUSSION: Regional anaesthesia was the key determinant of improved postoperative pain control, and intra-operative opioids added little additional benefit when regional techniques provided adequate coverage. Without regional anaesthesia, neither opioid-free nor opioid-inclusive strategies showed consistent analgesic superiority. However, opioid-free techniques reduced postoperative nausea and vomiting. These findings support preferential use of regional anaesthesia where feasible and suggest that avoiding intra-operative opioids may facilitate recovery, particularly when regional techniques are employed effectively.