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Category: Basic Sciences/Biologics; Ankle; Diabetes; Midfoot/Forefoot Introduction/Purpose: Charcot neuropathic arthropathy (CNA) is a debilitating, rapidly destructive degenerative joint disease that occurs in diabetic, neuropathic midfoot. Clinicoradiologic assessment for CNA previously relied on Eichenholtz Stage. There is limited data on CNA histopathology. The goal of this study was to independently develop a histopathologic scoring system for Charcot neuropathic arthropathy. Methods: Retrieval of surgical pathology specimens from neuroarthropathic CNA patients (2012-2019) were analyzed to evaluate joint soft tissue and bone. Considering progression from large to small periarticular bone fragments to resolution, we devised and applied a CNA FEMASK-score (named after coauthors): 0= intraneural arteriolosclerosis; 1= large bone fragments without host histiocytic response; 2= mixed bone fragments with host histiocytic response; 3= small minute bone spicules resorption to fibrosis. Clinical modified Eichenholtz staging and outcome were then compared the CNA FEMASK-score to assess for associations between these three elements. Results: Forty-eight cases of CNA included 34 males and 14 females, mean age 60.3 and age range 28-83 years, with clinical diabetes mellitus (predominantly Type II) and longstanding neuropathy. Elevated HbA1C, Eichenholtz stage, American Society of Anesthesia score, and Charlson comorbidity index were predictive of amputation. Pathologic specimens varied from fixation tissue to amputation. In addition to neurotraumatic, neurovascular and inflammatory findings, a distinctive intraneural hyalinized arteriolosclerosis was observed. FEMASK-scores:1 = 10%, 2= 58%, and 3=32%. FEMASK-score comparisons were 98% accurate compared with the modified Eichenholtz criteria scores of each patient and 98% reproducible among pathologists. FEMASK 2 and 3 correlates strongly with amputation. Conclusion: Our novel CNA FEMASK-score classification, derived from the largest cohort of diabetic neuropathic specimens, is reproducible, explains pathophysiology, correlates with Eichenholtz, and predicts amputation. The unique intraneural vasculopathy observed contributes to CNA etiology.