Background:In patients with diabetes mellitus, painful diabetic peripheral neuropathy (PDPN) is a frequent complication and can cause poor quality of life. We compared the efficacy and safety of duloxetine with those of gabapentin in patients with PDPN through a systematic review and meta-analysis of randomised controlled trials. MaterialsandMethods:PubMed, Embase and the Cochrane Library were searched for eligible studies published from database inception to January 2021. Visual Analogue Scale (VAS), sleep interference score, Clinical Global Impression of Change (CGIC), Patient Global Impression of Change (PGIC), Diabetic Neuropathy Symptom (DNS) score, Diabetic Neuropathic Examination (DNE) score, Neuropathic Disability Score (NDS) and side effects were used to compare duloxetine and gabapentin in patients with PDPN. Results:Three eligible randomised controlled trials involving 290 patients were included. No significant differences were observed between patients receiving duloxetine and gabapentin with respect to VAS (mean change difference = −1.23, 95% CI, −6.09 to 3.62; P = .62), sleep interference score (mean change difference = 0.42, 95% CI, −0.15 to 1.00; P = .15), CGIC (mean difference = 0.04, 95% CI, −0.11 to 0.20; P = .60), PGIC (mean difference= 0.24, 95% CI, −0.13 to 0.60; P = .21), DNS (mean change difference = 0.14, 95% CI, −0.35 to 0.63; P = .58), DNE (mean change difference = 0.26, 95% CI, −0.35 to 0.86; P = .41) and NDS (mean change difference = 0.30, 95% CI, −0.02 to 0.63; P = .07).Conclusions:No significant differences were observed in the efficacy of duloxetine and gabapentin when treating patients with PDPN.