OBJECTIVES: One of the most common complications of diabetes is painful diabetic peripheral neuropathy (PDPN), which has been increasing in prevalence.  Published guidelines recommend a number of medications to treat PDPN providing clinicians with a variety of treatment options. There have been multiple cost effectiveness studies comparing pregabalin to other antidepressant medications such as duloxetine and despiramine. However, there has not been a study that compares the cost effectiveness of pregabalin and venlafaxine. This research aims to compare the quality adjusted life year, costs, and cost effectiveness of Pregabalin vs. Venlafaxine. METHODS: Published and unpublished clinical trial ad cross-sectional data were integrated into a decision analytic model to estimate the costs of treatment for painful diabetic neuropathy over 3-month (base case), 1-month and 6-month time frames used for sensitivity analysis. Efficacy was measured by using quality adjusted life years (QALYs), and costs were measured in $US, using a third party payer perspective.  RESULTS: Pregabalin is more effective and less expensive than Venlafaxine in the base case analysis and through a range of sensitivity analysis. The incremental cost-effectiveness ration (ICER) for pregabalin relative to venlafaxine was $US4552.60 per QALY. CONCLUSIONS: Pregabalin is more cost effective than Venlafaxine for treating painful diabetic neuropathy, depending on the willingness to pay threshold. The estimated value of pregabalin and venlafaxine depends on the assumptions made in the statistical analyses.