OBJECTIVES: Patients with painful diabetic neuropathy (PDN) often do not respond to treatment and require frequent therapy switches. The objective of this study was to determine the cost-effectiveness of all possible PDN treatment pathways with desipramine (DES), duloxetine (DUL), gabapentin (GABA), and pregabalin (PRE) over a 10-year time horizon from a third-party payer perspective. METHODS: A microsimulation health-state transition model was created to estimate the direct healthcare costs and quality-adjusted life-years (QALYs) in 10,000 hypothetical patients with moderate-to-severe PDN. The model compared each of the 24 possible PDN treatment pathways, which consisted of initial treatment with DES, DUL, GABA, or PRE followed by therapy switches to remaining agents after therapy failure or serious adverse events. Medication adherence values and pain relief scores were specific to each treatment and thus changed as patients progressed through each pathway. Healthcare costs and health state utilities were assigned based on pain response (i.e. moderate-to-severe vs. mild) and were derived from national sources and published estimates. RESULTS: Five treatment pathways were not dominated (listed in order of increasing cost): 1) DES/DUL/GABA/PRE, 2) DUL/DES/GABA/PRE, 3) DUL/GABA/DES/PRE, 4) DUL/PRE/DES/GABA and 5) DUL/PRE/GABA/DES. Mean costs ranged from $29,200 to $35,700. Mean QALYs ranged from 3.09 to 3.13. Using DES/DUL/GABA/PRE as the reference, DUL/DES/GABA/PRE had the lowest incremental cost-effectiveness ratio ($1,190 per QALY gained). Deterministic sensitivity analyses showed the model was most sensitive to changes in health state utilities, medication adherence, and pain relief threshold. Probabilistic sensitivity analyses estimated that DUL/DES/GABA/PRE was cost-effective in 66% and 73% of the simulations at willingness-to-pay thresholds of $50,000 and $100,000 per QALY gained, respectively. CONCLUSIONS: Initiating treatment with DUL followed by DES, GABA, and PRE (in that order) after therapy failure appears to be the most cost-effective PDN treatment pathway. These results could help guide provider and third-party payer decisions surrounding PDN therapy management.