ABSTRACT: BACKGROUND:Regional anesthesia may mitigate the risk of persistent postoperative pain (PPP). This Cochrane review, published originally in 2012, was updated in 2017. METHODS:We updated our search of Cochrane CENTRAL, PubMed, EMBASE and CINAHL to December 2017. Only RCTs investigating local anesthetics (by any route) or regional anesthesia versus any combination of systemic (opioid or non-opioid) analgesia in adults or children, reporting any pain outcomes beyond three months were included. Data were extracted independently by at least two authors, who also appraised methodological quality with Cochrane 'Risk of bias' assessment and pooled data in surgical subgroups. We pooled studies across different follow-up intervals. As summary statistic, we reported the odds ratio (OR) with 95% confidence intervals and calculated the number needed to benefit (NNTB). We considered classical, Bayesian alternatives to our evidence synthesis. We explored heterogeneity and methodological bias. RESULTS:40 new and seven ongoing studies, identified in this update, brought the total included RCTs to 63. We were only able to synthesize data from 39 studies enrolling 3027 participants in a balanced design. Evidence synthesis favored regional anesthesia for thoracotomy (OR 0.52 [0.32 to 0.84], moderate-quality evidence), breast cancer surgery (OR 0.43 [0.28 to 0.68], low-quality evidence), and cesarean section (OR 0.46, [0.28 to 0.78], moderate-quality evidence). Evidence synthesis favored continuous infusion of local anesthetic after breast cancer surgery (OR 0.24 [0.08 to 0.69], moderate-quality evidence), but was inconclusive after iliac crest bone graft harvesting (OR 0.20, [0.04 to 1.09], low-quality evidence). CONCLUSIONS:Regional anesthesia reduces the risk of PPP. Small study size, performance, null, and attrition bias considerably weakened our conclusions. We cannot extrapolate to other interventions or to children.