OBJECTIVES: Diabetic Peripheral Neuropathic Pain (DPNP) is a chronic neuropathic condition that significantly affects both health-related quality of life and functional status, causing depression and disabilities, increased healthcare utilization and high costs. We aimed to perform an economic evaluation of three recommended first-line medications for DPNP. METHODS: The analysis was conducted using a three-month decision model, which compares duloxetine 60mg once daily (DUL), gabapentin 600mg 3-times daily (GAB) and pregabalin 150mg twice daily (PRE) for patients with DPNP and moderate to severe pain, under the perspective of public healthcare system in Mexico. Efficacy rates were gathered from published literature. Adherence (based in number of daily doses needed) and adverse effects (AE) rates were incorporated into the model. Direct medical costs included drug acquisition and additional medical consultation due to lack of efficacy (poor pain relief) or intolerable AE. Unit costs were taken from local public tariffs. All costs were calculated in 2009 Mexican Pesos (MXP) and then expressed in USD. Proportion of patients with Good Pain Relief (GPR) and expected quality-adjusted life years (QALY) by patient was assessed. RESULTS: Branded GAB and PRE were both dominated by generic GAB and DUL. Compared to branded GAB and PRE, DUL leads to savings of 98 and 129 USD per patient, respectively. The incremental cost per QALY gained with DUL used instead of generic GAB is 8821 USD. This amount is similar to the estimated gross domestic product per capita in Mexico during 2008 year. DUL was cost-effective compared to generic GAB in about 83% of the samples during a second-order Monte Carlo simulation. CONCLUSIONS: DUL had lower costs and better health outcomes when compared to both branded GAB and PRE. According to the recommendations stated by the World Health Organization, DUL can be seen as a cost-effective intervention compared to generic GAB.