Background This study examined whether changes in self-efficacy explain the effects of a mailed print intervention on long-term dietary practices of breast and prostate cancer survivors. The relationship between change in self-efficacy and long-term physical activity (PA) also was examined. Methods Breast and prostate cancer survivors (N = 543) from 39 US states and two Canadian provinces participated in the FRESH START intervention trial. Participants were randomly assigned to receive a 10-month program of mailed print materials on diet and PA available in the public domain or a 10-month program of tailored materials designed to increase fruit and vegetable (F&V) intake, decrease fat intake, and/or increase PA. Changes in self-efficacy for F&V intake and fat restriction were analyzed as potential mediators of the intervention's effects on diet at 2-year follow-up. Because we previously found that change in self-efficacy for PA did not vary by group assignment, the relationship between change in self-efficacy and PA at 2-year follow-up was examined across study conditions. Results Results suggest that change in self-efficacy for fat restriction partially explained the intervention's effect on fat intake (mean indirect effect = -0.28), and change in self-efficacy for F&V consumption partially explained the intervention's effect on daily F&V intake (mean indirect effect =.11). Change in self-efficacy for fat restriction partially accounted for the intervention's impact on overall diet quality among men only (mean indirect effect = 0.60). Finally, change in self-efficacy for PA predicted PA at 2-year follow-up. Conclusions Findings suggest that self-efficacy may influence long-term maintenance of healthy lifestyle practices among cancer survivors. Copyright © 2012 John Wiley & Sons, Ltd. Copyright © 2012 John Wiley & Sons, Ltd.