Objective: To quantify polyneuropathy impairments and comorbidities utilizing the Rochester Epidemiology Project (2010 census 5 148,201).Methods: ICD-9-CM coding identified polyneuropathy cases (2006)(2007)(2008)(2009)(2010) and their 5:1 age-and sex-matched controls. Mortality and impairments were evaluated while identifying and adjusting for Charlson Index comorbidities.Results: Overall prevalence of polyneuropathy was 1.66%, and markedly rose to 6.6% in persons older than 60 years. Cases (n 5 2,892) had more comorbidities than controls (n 5 14,435) with higher median Charlson Index (6 vs 3, p , 0.001). Diabetes with end-organ disease represented the largest increased comorbidity in cases compared with controls (46.8% vs 6.5%). Diabetic polyneuropathy was the most common specific subtype (38.2%). Miscoded idiopathic cases and false-negative controls also commonly had diabetic polyneuropathy. Median modified Rankin Scale score was considerably higher for cases than controls (4 vs 1, p , 0.001). Multiple comorbidities were found associated with polyneuropathy after adjusting for diabetes co-occurrence, including pulmonary disease, dementia, and others. Polyneuropathy was an independent contributor to multiple functional impairments including difficulty walking (odds ratio [OR] 5 1.9), climbing stairs (OR 5 2.0), using an assistive device (OR 5 2.0), fall tendency (OR 5 2.4), work disability (OR 5 4.2), lower limb amputations (OR 5 3.9), and opioid use (OR 5 2.7). Prevalent cases had a younger median age at death than controls (80 vs 86 years, p , 0.001), and incident cases had a 6-month shorter survival. Conclusions:Polyneuropathies have notable neurologic impairments beyond their identified multiple comorbidities. Life expectancy is shortened. Diabetic polyneuropathy is underidentified. The quantified extent of the disease burden and refined comorbidity associations emphasize that greater research efforts and health care initiatives are needed. Neurology ® 2015;84:1644-1651 GLOSSARY ADL 5 activities of daily living; CI 5 confidence interval; CPT 5 current procedural terminology; ICD-9-CM 5 International Classification of Diseases, Ninth Revision, Clinical Modification; IQR 5 interquartile range; mRS 5 modified Rankin Scale; OR 5 odds ratio; REP 5 Rochester Epidemiology Project.