BACKGROUND This study aimed to retrospectively assess and compare the safety and efficacy of sufentanil and fentanyl in the treatment of patients with traumatic brain injury. MATERIAL AND METHODS A total of 85 patients with traumatic brain injury from June 2016 to September 2018 were included in this study, and were enrolled into a sufentanil group and a fentanyl group according to different treatment methods. The patients in both groups were assessed with the Critical care Pain Observation Tool (CPOT) for analgesic score, and Richmond Agitation-Sedation Scale (RASS) for sedation score. RESULTS The scores of CPOT and RASS in the 2 groups were significantly lower than before treatment (P<0.05), but there was no significant difference between the 2 groups (P>0.05). The heart rate (HR), rate of spontaneous respiration (RR), and mean arterial pressure (MAP) of the 2 groups were significantly lower than before treatment (P<0.05), and the RR of the sufentanil group was significantly lower than that of the fentanyl group at all time points after treatment (P<0.001). CONCLUSIONS Sufentanil has a rapid onset of effect, and it is safe, stable, and effective for patients with traumatic brain injury in the intensive care unit (ICU). Compared with fentanyl, sufentanil can also effectively shorten mechanical ventilation time, time to obtain satisfactory sedation and analgesia, and the length of hospitalization in the ICU.