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The NCPD test for this article is available online only at the journal website, jwocnonline.com, and the test can be taken online at NursingCenter.com. PURPOSE: The purpose of this study was to investigate the risk factors for major amputation in persons hospitalized with diabetic foot ulcers involving the midfoot. DESIGN: Retrospective study. SUBJECTS AND SETTING: Between January 2003 and May 2019, a total of 1931 patients with diabetes were admitted to the diabetic wound center for the management of foot ulcers. Among the admitted patients, 169 patients with midfoot ulcers were included in this study. One hundred fifty-four patients (91%) healed without major amputation, while 15 patients (9%) healed post–major amputation. METHODS: Data related to 88 potential risk factors including demographics, ulcer condition, vascularity, bioburden, neurology, and serology were collected from patients in these 2 groups for comparison. Univariate and multivariate logistic regression analyses were performed to analyze risk factors for major amputation. RESULTS: Among the 88 potential risk factors, 15 showed statistically significant differences between the 2 groups. Using univariate analysis of 88 potential risk factors, 8 showed statistically significant differences. Using stepwise multiple logistic regression analysis, 3 of the 8 risk factors remained statistically significant. Multivariate-adjusted odds ratios for deep ulcers invading bone, cardiac disorders, and Charcot foot were 26.718, 18.739, and 16.997, respectively. CONCLUSION: The risk factors for major amputation in patients hospitalized with diabetic midfoot ulcers included deep ulcers invading the bone, cardiac disorders, and Charcot foot.