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Category: Diabetes, Hindfoot, Midfoot/Forefoot Introduction/Purpose: Charcot arthropathy is a destructive joint disorder in patients with longstanding neuropathy, commonly related to Type II diabetes (T2DM). The diagnosis is historically classified via the radiologic Eichenholtz staging system (E-score). The purpose of this study is to examine histopathologic features and develop a correlative pathologic score for Charcot neuroarthropathy. Methods: Patients undergoing lower limb surgery with a clinical diagnosis of midfoot-ankle Charcot neuroarthropathy were included for study. Clinical data, radiology, E-score (1-3), and surgical pathology specimens were reviewed to evaluate skin, adipose, vessel, skeletal muscle, nerve, bone, and bone fragments embedded in synovium. Charcot pathology-score 1 (P-score, CPSI) = large bone fragments (> half 40x hpf objective) without host histiocytic response. CPSII = mixed large and small bone fragments with/without host histiocytic response, CPSIII = small to minute spicules to almost complete resorption/absence of bone fragments with histiocytic/fibrosis-reactive response, were scored by the authors in a blinded fashion. Results: Forty-two patients (32 males and 10 females) were included in analyses with a mean age of 59.9 years (median age: 60, range 28-83). Clinical risk factors for Charcot included T2DM and longstanding neuropathy. Elevated HbA1C, E-Score, preoperative American Society of Anesthesia score, and Charlson comorbidity index were predictors of amputation. Majority of pathologic specimens examined had superficial ischemic ulceration, dermal fibrosis, cellulitis, medial hypertrophy, atherosclerosis, skeletal muscle atrophy, and nerve hypertrophy with intraneural edema and perineural fibrosis. Osteomyelitis was present in >70%. P-scores CPSI = 6%, CPSII = 44%, CPSIII = 50% correlate with E-scores in 98% of cases without interobserver variability. Minor difference from E-score to P-score (2%) was due to sampling. Novel neuropathy change includes observation of intraneural vasculopathy (arteriolosclerosis) in evaluable nerves. Conclusion: CPS is reliable and reproducible and can be performed with adequate synovial sampling. Charcot progresses from large bone fragments in synovium to mixed size with histiocytic response, and final small/resorbed fragments with marked host response/fibrosis. Intraneural vasculopathy likely plays a role in Charcot. Charcot pathology-score (P-score) strongly correlates with clinicoradiologic Eichenholtz-score (E-score).