Objective: Neuropathic pain is a chronic condition that causes functional impairment in many areas of life and it occurs frequently with diabetes. The aim of this study was to analyze the cost-effectiveness of different treatments in managing diabetic peripheral neuropathy from the health care payer's perspective. Methods: A four-state stochastic Markov model was performed to estimate costs and effectiveness. The Markov model includes several stages related to functional disability (mild-pain, moderate-pain, severe-pain and death). Effectiveness was assumed as the percentage of patients with no or mild pain (pain score <4) at the end of the follow-up period (one-year).Transition probabilities were taken from national and international published literature. Comparators used in the assessment were carbamazepine (200-600mg/day), amitriptyline (100-150mg/day), gabapentin (2400-3600mg/day) and pregabalin (300-600mg/day). Resource use and costs were obtained from hospital records (n=1000) from the Social Security Mexican Institute (IMSS) and official institutional databases. Costs include emergency, out-patient and inpatient services, drugs, procedures, etc. The model was calibrated. Probabilistic sensitivity analyses were performed employing bootstrapping techniques and acceptability curves were constructed. Results: The highest percentage of patients with no or mild pain during the follow-up period was obtained by pregabalin (59.6%;CI95% 59.0%–60.2%); followed by gabapentin (49.2%; CI95% 48.7%–49.7%); amitriptyline (47.6%;CI95% 47.1%–48.1%) and carbamazepine (34.4%;CI95% 34.1%–34.8%). The annual expected mean costs per patient were US$3001.4 (CI95% US$2956.4-US$3046.3); US$4,707.7 (CI95% US$4689.9-US$4723.6); US$2814.4 (CI95% US$2783.4-US$2845.5) and US$3701.9 (CI95% US$3687.2-US$3716.6); respectively following the order above. The ICER's of pregabalin vs. carbamazepine (baseline), gabapentin and amitriptyline were -US$700.5 (CI95% -US$670.4:-US$730.7), -US$1706.4 (CI95% -US$1677.3:-US$1733.4) and US$186.9 (CI95% US$173.1-US$200.8); respectively. Using acceptability curves (WTP US$5000-US$50,000), pregabalin showed a probability between 90-99% to be the treatment most cost-effective. Conclusion: In Mexico, pregabalin showed to be a cost-saving therapy when is compared with carbamazepine and gabapentin; and cost-effective vs. amitriptyline in the management of neuropathic pain.