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Background: This RCT investigated the effect of opioid titration by three different nociception monitoring devices or clinical signs during general anaesthesia., Methods: Ninety-six patients undergoing radical retropubic prostatectomy with propofol/remifentanil anaesthesia were randomised into one of four groups to receive remifentanil guided by one of three nociception monitoring devices (surgical pleth index [SPI], pupillary pain index [PPI], or nociception level [NOL]) or by clinical judgement (control). Intraoperative remifentanil requirement was the primary endpoint, whereas recovery parameters and stress hormone levels were secondary endpoints., Results: The mean [95% confidence interval {CI}] remifentanil administration rate differed between the groups: control 0.34 (0.32-0.37), SPI 0.46 (0.38-0.55), PPI 0.07 (0.06-0.08), and NOL 0.16 (0.12-0.21) μg kg -1 min -1 (P<0.001). Intraoperative cessation of remifentanil administration occurred in different numbers (%) of patients: control 0 (0%), SPI 1 (4.3%), PPI 18 (75.0%), and NOL 11 (47.8%); P=0.002. The area under the curve analyses indicated differences in cumulative cortisol levels (mg L -1 min -1 ) amongst the groups: control 37.9 (33.3-43.1), SPI 38.6 (33.8-44.2), PPI 72.1 (63.1-82.3), and NOL 54.4 (47.6-62.1) (mean [95% CI]). Pairwise group comparison results were as follows: control vs SPI, P=0.830; control vs PPI, P<0.001; control vs NOL, P=0.001; SPI vs PPI, P<0.001; SPI vs NOL, P=0.002; and PPI vs NOL, P=0.009., Conclusions: The nociception monitoring devices and clinical signs reflect the extent of nociception differently, leading to dissimilar doses of remifentanil. Very low remifentanil doses were associated with an increase and higher remifentanil doses were accompanied by a decrease in serum cortisol concentrations. Use of nociception monitoring devices for guiding intra-operative opioid dosing needs further validation., Clinical Trial Registration: NCT03380949., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)