OBJECTIVES: The efficacy and safety of capsaicin 8% patch (Qutenza) for treating painful diabetic peripheral neuropathy (PDPN) has recently been studied but direct comparison with other treatments is lacking.  The objective was to obtain estimates of the relative efficacy and safety of oral treatments for PDPN and capsaicin 8% patch. METHODS: A systematic literature review (SLR) and network meta-analysis (NMA) were conducted. The SLR collated data from all published randomized controlled trials (RCTs) comparing either pregabalin, duloxetine, amitryptiline or gabapentin. Efficacy data for capsaicin 8% patch was obtained from 12-week placebo-controlled RCT (STEP) and a 12-month open-label randomized study versus standard of care (PACE). Electronic databases (Embase, Medline, CRD-Dare and Cochrane) were searched up to February 2014. Search results were screened, eligible studies were assessed for risk of bias and data were extracted. Efficacy outcomes selected for Bayesian NMA (WinBUGS v.1.4) included responder status (≥30%/ ≥50% reduction in pain) and absolute change in pain score from baseline. Safety endpoints included nausea, diarrhoea, somnolence and dizziness. RESULTS: Out of the 400 unique records identified, 24 were eligible for inclusion in the review. Eight studies were included in the NMA for ≥30% pain reduction, 10 for ≥50% pain reduction, and 11 reporting pain score change.  No significant differences were observed between treatments regarding either responder rate based on ≥30%/ ≥50% pain reduction or pain score change from baseline. Scenario analyses considering different dosing regimens of pregabalin and duloxetine, different definitions of clinical endpoints and inclusion of PACE trial data did not significantly change the results. The capsaicin 8% patch exhibited none of the investigated safety events, whereas all orals reported dose-dependent side-effects. CONCLUSIONS: This NMA found that capsaicin 8% patch, pregabalin, duloxetine, and gabapentin do not have different efficacy profiles for PDPN; however, capsaicin 8% patch exhibits fewer systemic adverse events.