BACKGROUND AND OBJECTIVE: : Diabetic foot ulcer (DFU) is one of the main health challenges of diabetes complications worldwide. A wide range of factors may increase the risk of DFU. This study aimed to investigate the risk factors of DFU among diabetic patients. METHODS: This case-control study was conducted on 800 diabetic patients at the Tehran diabetes clinic of the Endocrinology and Metabolism Research Institute in Iran. The case group included 400 diabetic patients diagnosed with DFU, while the control group included 400 diabetic patients without DFU. Data were collected through medical records, validated questionnaires, and clinical examinations. The association between factors and the risk of DFU was analyzed using both crude and adjusted logistic regression models, adjusting for confounders based on a directed acyclic graphs. RESULTS: The final adjusted model demonstrated significant direct associations between the risk of DFU with a longer duration of diabetes, a history of previous DFU, peripheral neuropathy, retinopathy, high blood pressure, severe kidney function loss, and good foot self-care. However, there were significant inverse associations between DFU risk with female gender, higher education levels, being married, use of oral diabetes drugs, higher hemoglobin levels, and high physical activity. CONCLUSIONS: The risk of DFU was significantly associated with the following factors: diabetes duration, previous DFU history, peripheral neuropathy, retinopathy, blood pressure, kidney function, foot self-care, gender, education levels, marital status, diabetes drugs, hemoglobin levels, and physical activity. Further studies, especially ones in multicenter cohorts with a special focus on novel risk factors, are warranted to expand on our findings. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-025-01582-z.