© 2017 The Obesity Society Objective: Weight gain occurs commonly in young adults and increases the risk of cardiovascular disease (CVD). Following on a previous report that two self-regulation interventions reduced weight gain relative to control, this study examines whether these interventions also benefit CVD risk factors. Methods: The Study of Novel Approaches to Weight Gain Prevention was a randomized trial in two academic settings (N = 599; 18-35 years; BMI 21-30 kg/m2) comparing two interventions (Self-Regulation with Small Changes; Self-Regulation with Large Changes) and a control group. Small Changes taught participants to make daily small changes in calorie intake (approximately 100 calories) and activity. Large Changes taught participants to initially lose 5 to 10 pounds to buffer anticipated weight gains. CVD risk factors were assessed at baseline and at 2 years in 471 participants. Results: Although Large Changes was associated with more beneficial changes in glucose, insulin, and homeostatic model assessment of insulin resistance than Control, these differences were not significant after adjusting for multiple comparisons or 2-year weight change. Comparison of participants grouped by percent weight change from baseline to 2 years showed significant differences for several CVD risk factors, with no interaction with treatment condition. Conclusions: Magnitude of weight change, rather than specific weight gain prevention interventions, was related to changes in CVD risk factors in young adults.