© 2016 American Society for Nutrition. Background: Hormonal fluctuations during the menstrual cycle influence energy intake and expenditure as well as eating preferences and behavior. Objective: We examined the effect in healthy, overweight, premenopausal women of a diet and exercise weight-loss program that was designed to target and moderate the effects of the menstrual cycle compared with the effect of simple energy restriction. Design: A total of 60 healthy, overweight, premenopausal women were included in a 6-mo weight-loss program in which each subject consumed a diet of 1600 kcal/d. Subjects were randomly assigned to either a combined diet and exercise program that was tailored to metabolic changes of the menstrual cycle (Menstralean) or to undergo simple energy restriction (control). Results: Thirty-one women (19 Menstralean and 12 control women) completed the study [mean ± SD body mass index (in kg/m2): 32.0 ± 5.2]. Both groups lost weight during the study. In an intention-to-treat analysis, the Menstralean group did not achieve a clinically significant weight loss compared with that of the control group (P = 0.61). In per-protocol analyses, a more-pronounced weight loss of 4.3 ± 1.4 kg (P = 0.002) was shown in adherent Menstralean subjects than in the control group. Conclusion: A differentiated diet and exercise program that is tailored to counteract food cravings and metabolic changes throughout the menstrual cycle may increase weight loss above that achieved with a traditional diet and exercise program in women who can comply with the program. This trial was registered at clinicaltrials.gov as NCT01622114.