For decades, behavioral weight-loss treatments have been unsuccessful beyond the short term. Development and testing of innovative, theoretically based methods that depart from current failed practices is a priority for behavioral medicine. To evaluate a new, theory-based protocol in which exercise support methods are employed to facilitate improvements in psychosocial predictors of controlled eating and sustained weight loss. Women with obesity were randomized into either a comparison treatment that incorporated a print manual plus telephone follow-ups (n = 55) or an experimental treatment of The Coach Approach exercise-support protocol followed after 2 months by group nutrition sessions focused on generalizing self-regulatory skills from an exercise support to a controlled eating context (n = 55). Repeated-measures analysis of variance contrasted group changes in weight, physical activity, fruit and vegetable intake, mood, and exercise- and eating-related self-regulation and self-efficacy over 24 months. Regression analyses determined salient interrelations of change scores over both the weight-loss phase (baseline-month 6) and weight-loss maintenance phase (month 6-month 24). Improvements in all psychological measures, physical activity, and fruit and vegetable intake were significantly greater in the experimental group where a mean weight loss of 5.7 kg (6.1% of initial body weight) occurred at month 6, and was largely maintained at a loss of 5.1 kg (5.4%) through the full 24 months of the study. After establishing temporal intervals for changes in self-regulation, self-efficacy, and mood that best predicted improvements in physical activity and eating, a consolidated multiple mediation model suggested that change in self-regulation best predicted weight loss, whereas change in self-efficacy best predicted maintenance of lost weight. Because for most participants loss of weight remained greater than that required for health benefits, and costs for treatment administration were comparatively low, the experimental protocol was considered successful. After sufficient replication, physician referral and applications within health promotion and wellness settings should be considered.