Background <p>With the prevalence of leprosy dramatically declining, the focus of leprosy control has gradually shifted from the implementation of multidrug therapy (MDT) to accelerating the reduction of the disease burden and preventing disability. Southwestern China currently bears the highest leprosy burden in China and more than half of the disability cases reported every year are from this region. However, the potential risk factors of leprosy disability in this area remain unknown.</p> Methods <p>In this study, we evaluated the physical disabilities of 4578 leprosy patients in southwest China from 2010 to 2020. Clinical and epidemiological factors associated with physical disability resulting from leprosy were identified using multinomial logistic regression.</p> Results <p>A total of 4578 leprosy cases with complete information were reported in southwestern China during the 11 years. Among them, 1126 (24.60%) patients were diagnosed with grade 2 disability (G2D), and 737 (16.10%) were confirmed with grade 1 disability (G1D) at diagnosis. The potential factors associated with G2D are as follows: nerve damage, male, leprosy reaction, older age of the patient, the longer delay in diagnosis, and more skin lesions. Furthermore, nerve damage, leprosy reaction, male, older age, and longer delayed diagnosis were the main risk factors of G1D. Among them, nerve damage, older age, longer delayed diagnosis, male, and leprosy reaction were the common risk factors for G1D and G2D.</p> Conclusion <p>In our study, we found older age, longer delayed diagnosis, male, more skin lesions, more nerve lesions, and leprosy reactions were associated with leprosy disability. These findings provide a foundation for the development of targeted interventions aimed at the early identification of individuals at higher risk of physical disability, as well as for self-care and health education to promote timely medical consultation to prevent leprosy-related disabilities.</p>