Background Self-efficacy has important implications for health and functioning in people with limited mobility. However, the influence of self-efficacy on mobility in adults who use wheelchairs has yet to be investigated. Objective The study objective was to: (1) estimate the direct association between wheelchair use self-efficacy and life-space mobility and (2) investigate an indirect effect through wheelchair skills. Design This was a cross-sectional study. Methods Participants (N=124) were adults who use a wheelchair, live in the community, and were 50 years of age and older (X̅=59.67, range=50–84), with at least 6 months of experience with manual wheelchair use; 60% were men. The 20-item Life-Space Assessment, the 65-item Wheelchair Use Confidence Scale, and the 32-item Wheelchair Skills Test-Questionnaire were used to measure life-space mobility, self-efficacy, and wheelchair skills, respectively. Results Self-efficacy had a statistically significant association with life-space mobility (nonstandardized regression coefficient=0.23, 95% confidence interval=0.07, 0.39) after controlling for sex, number of comorbidities, geographic location, and assistance with using a wheelchair. This model accounted for 37.1% of the life-space mobility variance, and the unique contribution of self-efficacy was 3.5%. The indirect effect through wheelchair skills was also statistically significant (point estimate=0.21, 95% bootstrapped confidence interval=0.05, 0.43) and accounted for 91.3% of the direct effect of self-efficacy on life-space mobility. This model accounted for 39.2% of the life-space mobility variance. Limitations Causality could not be established because of the study design. The self-report nature of data from volunteers may be influenced by recall bias, social desirability, or both. Conclusions Wheelchair use self-efficacy had both direct and indirect associations with life-space mobility after controlling for confounding variables. Interventions targeted toward improving self-efficacy may lead to improvements in life-space mobility.