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Objective: To determine and compare specific factors that could be associated and predictive with successful prosthetic rehabilitation in major lower-limb amputations. Methods: A 15-year long (2000-2014) retrospective observational cohort study was conducted. Two different criteria were used to define successful prosthetic rehabilitation: (1) the ability to walk at least 45 m, regardless of assistive devices; and (2) walking >45 m without other ambulatory aids than one cane (if required). Age, gender, comorbidities, cause and level of amputation, stump characteristics, ulcers in the preserved limb, and time between surgery and physical therapy were examined as predictors of successful prosthetic rehabilitation. Results: A total of 169 patients (61.60±15.9 years) were included. Regarding walking ability with or without walking aids, the presence of ulcers in the preserved limb was individually associated with failed prosthetic rehabilitation (p < 0.001), while being male (OR = 0.21; 95%CI = 0.06-0.80) and transtibial level of amputation (OR = 6.73; 95%CI = 1.92-23.64) were identified as independent predictors of failure and success, respectively. Regarding the criterion of successful rehabilitation, a shorter time until rehabilitation was individually associated with improved walking ability (p < 0.013), while failure could be predicted by comorbidities (OR = 0.48; 95%CI = 0.29---0.78) and age groups of 65---75 years old (OR = 0.19; 95%CI = 0.05-0.78) and over 75 years old (OR = 0.19; 95%CI = 0.04-0.91). Conclusions: Regarding walking ability with or without walking aids, male gender and transtibiallevel of amputation are independently associated with failure and success respectively, whereasolder age and comorbidities can predict failed prosthetic rehabilitation when assistive walking devices are considered. Future prospective cohort studies are needed to confirm these findings.