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BACKGROUND: Perineural (PN) dexamethasone (DEX) administration can prolong the analgesic time of a brachial plexus block. However, its efficacy and safety are controversial due to its off-label use and different routes of administration. OBJECTIVES: This meta-analysis aimed to assess the safety and efficacy of PN versus intravenous (IV) dexamethasone. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). SETTING: Relevant studies were found through a comprehensive literature search of PubMed, Web of Science, Ovid, EMBASE, and the Cochrane Library (from the inception until January 2020). METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, this meta-analysis was conducted to identify RCTs comparing PN and IV dexamethasone in brachial plexus block. A randomized effect model was used in the meta-analysis and the subgroup analysis was performed with adrenaline stratification. The quality of evidence and the strength of recommendations were graded by GradePro version 3.6.1. RESULTS: Twelve RCTs with a total of 1,345 subjects were included. We found that PN dexamethasone could prolong the duration of analgesia (mean difference [MD]: 131.82 minutes, 95% confidence interval [CI] [38.96, 224.68], I2 = 82%, P = 0.005), motor block (MD: 218.85 minutes, 95% CI [113.65,324.05], I2 = 72%, P < 0.0001) and sensory block (MD: 209.57 minutes, 95% CI [72.64, 346.50], I2 = 87%, P = 0.003) in the main analysis with significant difference. In the absence of epinephrine, there were no significant differences between PN dexamethasone and IV dexamethasone. Except for adverse-effects, no significant differences were observed in secondary outcomes. PN dexamethasone had slightly higher adverse-effects; however, these could be altered if a sensitivity analysis was conducted. LIMITATIONS: There was high heterogeneity among included studies. CONCLUSIONS: PN dexamethasone can prolong the duration of analgesia, sensory block, and motor block, when compared with IV dexamethasone. In a subgroup analysis without epinephrine, the 2 routes of administration were equivalent to topical anesthesia. There were no differences in secondary outcomes, except for adverse effects, which could be altered if a sensitivity analysis was conducted. Therefore, despite the advantages of PN dexamethasone, caution is needed due to its off-label character. While the results of this study are promising, additional large and well-designed RCTs are needed to validate these initial findings and their implications. KEY WORDS: Analgesia, brachial plexus block, dexamethasone, intravenous, meta-analysis, perineural, randomized controlled trial