Background: Physical activity is associated with reductions in fatigue in breast cancer survivors. However, mechanisms underlying this relationship are not well-understood. The purpose of this study was to longitudinally test a model examining the role of self-efficacy and depression as potential mediators of the relationship between physical activity and fatigue in a sample of breast cancer survivors using both self-report and objective measures of physical activity. Methods: All participants (N = 1,527) completed self-report measures of physical activity, self-efficacy, depression, and fatigue at baseline and 6 months. A subsample was randomly selected to wear an accelerometer at both time points. It was hypothesized that physical activity indirectly influences fatigue via self-efficacy and depression. Relationships among model constructs were examined over the 6-month period using panel analysis within a covariance modeling framework. Results: The hypothesized model provided a good model-data fit (chi(2) = 599.66, df = 105, P <= 0.001; CFI = 0.96; SRMR = 0.02) in the full sample when controlling for covariates. At baseline, physical activity indirectly influenced fatigue via self-efficacy and depression. These relationships were also supported across time. In addition, the majority of the hypothesized relationships were supported in the subsample with accelerometer data (chi(2) = 387.48, df = 147, P <= 0.001, CFI = 0.94, SRMR = 0.04). Conclusions: This study provides evidence to suggest the relationship between physical activity and fatigue in breast cancer survivors may be mediated by more proximal, modifiable outcomes of physical activity participation. Impact: Recommendations are made relative to future applications and research concerning these relationships. (c) 2013 AACR.