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Mechanisms underlying the relationship between physical activity and quality of life (QOL) in breast cancer survivors are not well understood. The purpose of the present study was to longitudinally test a model examining self-efficacy and health status as potential mediators of this relationship.At baseline and 6 months, breast cancer survivors (n = 1527) completed physical activity, self-efficacy, health status, and QOL measures, and a subsample (n = 370) wore an accelerometer. Panel analysis within a covariance modeling framework was used to test the hypothesis that physical activity indirectly influences QOL across time.The hypothesized model provided a good fit in the full sample (χ2 = 409.06; d.f. = 91, p < 0.001; comparative fit index (CFI) = 0.98; standardized root mean residual (SRMR) = 0.04) and the accelerometer subsample (χ2 = 320.96, d.f. = 134, p < 0.001; CFI = 0.95; SRMR = 0.05), indicating that physical activity indirectly, via self-efficacy and health status indicators, influences QOL across time.Physical activity may influence QOL in breast cancer survivors through more proximal, modifiable factors. Copyright © 2013 John Wiley & Sons, Ltd.