Background: Due to conflicting evidence regarding first-line therapies for chronic post-surgical pain (CPSP), here we comparatively evaluated the efficacy and safety of first-line therapies for the prevention of CPSP. Materials and Methods: MEDLINE, EMBASE, and Cochrane CENTRAL databases were searched for randomized, controlled trials (RCTs) of systemic drugs measuring pain three months or more post-surgery. Pairwise meta-analyses (a frequentist technique directly comparing each intervention against placebo) and network metaanalyses (a Bayesian technique simultaneously comparing several interventions via an evidence network) compared the mean differences for primary efficacy (reduction in all pain), secondary efficacy (reduction in moderate or severe pain), and primary safety (drop-out rate from treatment-related adverse effects). Ranking probabilities from the network meta-analysis were transformed using surface under the cumulative ranking analysis (SUCRA). Sensitivity analyses evaluated the impact of age, gender, surgery type, and outlier studies. Results: Twenty-four RCTs were included. Mexiletine and ketamine ranked highest in primary efficacy, while ketamine and nefopam ranked highest in secondary efficacy. Simultaneous SUCRA-based rankings of the interventions according to both efficacy and safety revealed that nefopam and mexiletine ranked highest in preventing CPSP. Through the sensitivity analyses, gabapentin and ketamine remained the mosthighly- ranked in terms of efficacy, while nefopam and ketamine remained the mosthighly- ranked in terms of safety. Conclusions: Nefopam and mexiletine may be considered as first-line therapies for the prevention of CPSP. On account of the paucity of evidence available on nefopam and mexiletine, gabapentin and ketamine may also be considered. Venlafaxine is not recommended for the prevention of CPSP. ©Ning et al.