BACKGROUND: Interventions targeting psychosocial factors may improve rehabilitation outcomes for prosthesis users after lower-limb amputation (LLA), but there is a need to identify targeted factors for minimizing disability. OBJECTIVE: To identify psychosocial factors related to disability for prosthesis users after LLA in middle age or later. DESIGN: Cross-sectional study. SETTING: General community. PARTICIPANTS: Participants with LLA (N = 122) were included in this cross-sectional study if their most recent LLA was at least 1 year prior, they were ambulating independently with a prosthesis, and they were between 45 and 88 years old. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Disability, the primary outcome, was measured using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS). Candidate psychosocial variables included self-efficacy, social support, and motivation, measured using the Self-Efficacy of Managing Chronic Disease questionnaire (SEMCD), Multidimensional Scale of Perceived Social Support questionnaire (MSPSS), and modified contemplation ladder (mCL), respectively. The hypothesis was that greater self-efficacy, social support, and motivation would be associated with lower disability when controlling for covariates. RESULTS: The covariate model, including etiology, age, sex, U.S. military veteran status, LLA characteristics, time since LLA, medical complexity, and perceived functional capacity, explained 66.1% of disability variability (WHODAS 2.0). Backward elimination of candidate psychosocial variables stopped after removal of motivation (P = .10), with self-efficacy (P < .001) and social support (P = .002) variables remaining in the final model. The final model fit was statistically improved (P < .001) and explained an additional 6.1% of disability variability when compared to the covariate model. CONCLUSIONS: Greater self-efficacy and social support are related to lower disability after LLA. Findings suggest there may be a role for interventions targeting increased physical function, self-efficacy, and social support for ambulatory prosthesis users after LLA in middle age or later, especially when complicated by multiple chronic conditions.