BACKGROUND: Long-term (≥12 months) randomized trials evaluating the efficacy of intermittent fasting (IMF) as a dietary weight loss strategy are limited. Furthermore, no studies have compared IMF versus daily caloric restriction (DCR) when both interventions are provided in the context of a guidelines-based behavioral weight loss program. OBJECTIVE: To compare the effects of 4:3 IMF versus DCR on changes in weight at 12 months, with comprehensive behavioral support provided to both groups. DESIGN: Randomized clinical trial. (ClinicalTrials.gov: NCT03411356). SETTING: Denver, Colorado, and surrounding metropolitan area. PARTICIPANTS: Adults aged 18 to 60 years with body mass index (BMI) of 27 to 46 kg/m INTERVENTION: The IMF group was instructed to restrict energy intake by 80% on 3 nonconsecutive days per week, with ad libitum intake (no restriction) the other 4 days (4:3 IMF). The DCR group was instructed to reduce daily energy intake by 34% to match the weekly energy deficit of 4:3 IMF. Both groups received a high-intensity comprehensive behavioral weight loss program that included group-based behavioral support and a recommendation to increase moderate-intensity physical activity to 300 minutes per week. MEASUREMENTS: The primary outcome was change in body weight (in kilograms) at 12 months. RESULTS: Of the 165 (4:3 IMF, LIMITATION: Limited generalizability. CONCLUSION: Compared with DCR, 4:3 IMF resulted in modestly greater weight loss among adults with overweight or obesity enrolled in a 12-month, high-intensity, comprehensive behavioral weight loss program. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases.