OBJECTIVES: To perform an economic evaluation of duloxetine, pregabalin and (either branded or generic) gabapentin for managing pain in patients with painful diabetic peripheral neuropathy (PDPN) in Mexico. METHODS: The analysis was conducted using a three-month decision model, which compares duloxetine 60mg once daily (DUL), pregabalin 150mg twice daily (PGB) and gabapentin 600mg three-times daily (GBP) for patients with PDPN and moderate-to-severe pain, under the perspective of the Mexican public healthcare system. We performed a systemic review and calculated placebo-adjusted risk ratios for achieving good pain relief (GPR), any adverse event (AE) and withdrawal owing to intolerable AE. Direct medical costs included drug acquisition and additional visits due to lack of efficacy (poor pain relief) or intolerable AE. Unit costs were taken from local sources. Adherence rates (based in number of daily doses needed) were used to estimate the expected drug costs. All costs are expressed in 2010 USD (1USD:12.50MXN Pesos). Utility values drawn from published literature were applied to health states. Proportion of patients with GPR and quality-adjusted life years (QALY) were assessed. RESULTS: Branded-GBP was dominated by all the other options. PGB was more costly and less effective than DUL. Compared with branded-GBP and PGB, DUL led to savings of $80,080 and $85,920 (per 1000 patients) USD. The incremental cost per QALY gained with DUL used instead of generic-GBP was $8,194. This amount is slightly lower than the estimated gross domestic product per capita in Mexico for 2010. During a second-order Monte Carlo simulation, DUL had the highest probability of being cost-effective (61%), followed by generic-GBP (25%) and PGB (14%). CONCLUSIONS: This study suggests that DUL provides overall savings and better health outcomes compared with branded-GBP and PGB. Administering DUL rather than generic-GBP is a highly cost-effective intervention to manage PDPN in Mexico.