This prospective observational study included 80 adults (>18 years) patients admitted to the intensive care unit who were unconscious (Glasgow Coma Scale [GCS] score < 9 with a motor response < 5) and receiving mechanical ventilation. A tetanic stimulation was used to assess nociception; automated pupillometry (Algiscan, ID-MED, France) was used to compute the pupillary pain index score (PPI), with a PPI > 4 considered as nociception. Concomitantly, the number of skin conductance fluctuations (NSCF) per second, measured using a Skin Conductance Algesimeter (SCA, MEDSTORM Innovation AS, Norway; > 0.27 fluctuations/sec indicating nociception), and the instantaneous Analgesia Nociception Index (iANI, MDoloris Medical Systems, France; < 50 indicating nociception) were collected. Tetanic stimulation resulted in a median pupillary dilation of 16 [6-25] % and a PPI of 5 [2-7]. According to the PPI assessment, 44 patients (55%) had nociception, whereas 23 (29%) and 18 (23%) showed nociception according to the algesimeter and iANI assessment, respectively. No significant changes in measured physiologic variables were observed after the tetanic stimulation. There were no correlations between PPI, post-stimulation iANI, and SCA-derived variables. There were no differences in PPI, iANI, and SCA variables in patients with low and normal baseline EEG power at baseline. PERSPECTIVES: Detection of nociception varies across different devices in unconscious critically ill patients. Further studies are required to understand which method to implement for analgesic administration in this patient population.