Purpose <p>Diabetic peripheral neuropathy (DPN) is one of the leading complications of diabetes. Given the significant growth in prevalence of diabetes and therefore DPN in the United States in recent years, a quantitative analysis is needed to estimate the annual cost burden of DPN.</p> Methods <p>A cost-of-illness burden model was created to estimate the cost burden on DPN in the United States. A review of the literature was undertaken to identify the most appropriate epidemiologic and economic inputs. One-way sensitivity analyses were conducted for every model input parameter to show the potential variability in the estimated cost-burden.</p> Results <p>There is an estimated prevalence of approximately 13,209,600 patients with DPN in the U.S., with an estimated annual cost burden from DPN of $45,930,580,972. Of the estimated cost burden, $30,859,424,749 was from DPN specific care ($2,389,038,060 for outpatient office visits, $26,830,282,752 for inpatient hospitalizations, and $1,640,103,936 from prescription medications) and $15,071,156,223 from treating incident DPN complications ($12,875,200,000 for diabetic foot ulcers and $2,195,956,223 for diabetic lower limb amputations).</p> Conclusions <p>DPN is a very costly condition, and the burden is expected to continue to grow in the coming years.</p>