Objectives: The objective of this prospective, single-site, 2-year dietary intervention study was to evaluate the effects of moderate weight reduction and subsequent partial weight regain on cardiovascular structure and function. Background: Obesity is associated with adverse cardiac and vascular structural and functional alterations. Methods: Sixty obese subjects (age 46 ± 10 years, body mass index 37 ± 3 kg/m2) were evaluated during their participation in a weight loss study. Cardiac and vascular ultrasound studies were performed at baseline and at 3, 6, 12, and 24 months after start of intervention. Results: Forty-seven subjects (78%) completed the entire 2-year follow-up. Average weight loss was 7.3 ± 4.0%, 9.2 ± 5.6%, 7.8 ± 6.6%, and 3.8 ± 7.9% at 3, 6, 12, and 24 months, respectively. Age- and sex-adjusted mixed linear models revealed that the follow-up time was significantly associated with decreases in weight (p < 0.0001), left ventricular (LV) mass (p = 0.001), and carotid intima-media thickness (p < 0.0001); there was also significant improvement in LV diastolic (p ≤ 0.0001) and systolic (p = 0.001) function. Partial weight regain diminished the maximal observed beneficial effects of weight loss, however cardiovascular parameters measured at 2 years still showed a net benefit compared with baseline. Conclusions: Diet-induced moderate weight loss in obese subjects is associated with beneficial changes in cardiovascular structure and function. Subsequent weight regain is associated with partial loss of these beneficial effects. (The Safety and Effectiveness of Low and High Carbohydrate Diets; NCT00079547). © 2009 American College of Cardiology Foundation.