BackgroundWhile numerous studies have examined the influence of perineural dexamethasone on nerve block duration, its potential impact on postoperative nerve injury has not been adequately addressed. ObjectiveThis study aims to elucidate the effect of perineural dexamethasone on nerve injury and nerve function recovery after surgery. DesignA prospective randomized double-blinded trial. SettingThe First Affiliated Hospital of Chengdu Medical College, Chengdu, China. The study was conducted between 14 June and 30 December 2022. ParticipantsPatients aged 18 – 80 years, ASA I - II, scheduled for elective orthopedic or burn and plastic surgery. InterventionsPatients were randomized to receive either perineural dexamethasone (D group) or no dexamethasone (ND group). Main outcome measuresPrimary outcomes were the incidence and recovery of nerve injury. Secondary outcomes included postoperative pain scores, analgesic consumption, and adverse events. ResultsInitial postoperative nerve injury rates were similar between groups (D: 30.4 %, ND: 33.3 %, P > 0.05). At 12 weeks post-discharge, significantly more patients in the ND group recovered from nerve deficits (78.8 % vs 60.3 %; OR = 2.45, 95 % CI = 1.05 – 5.72, P < 0.05). No significant differences were observed in postoperative hyperglycemia or surgical site infection rates. ConclusionPerineural dexamethasone may impede nerve function recovery, suggesting caution in its use, particularly for patients with pre-existing nerve damage or diabetes. Further research is needed to elucidate the long-term effects of dexamethasone on nerve tissue recovery. Trial registrationchictr.org.cn, ChiCTR2200059424.