© 2014 The Obesity Society. Objective: To investigate the variations in body weight, food intake, and body composition of both male and female C57BL/6J mice during a diet-induced obesity model with high-fat diet (HFD) feeding. Methods: Mice were individually housed and fed ad libitum either a low-fat diet (LFD, 10% calories from fat; n = 15 male, n = 15 female) or HFD (45% calories from fat; n = 277 male, n = 278 female) from 8 to 43 weeks of age. Body weight, food intake, and body composition were routinely measured. Results: Body weight was significantly increased with HFD (vs. LFD) in males from week 14 (P = 0.0221) and in females from week 27 (P = 0.0076). Fat mass and fat-free mass of all groups were significantly increased over time (all P<0.0001), with a large variation observed in fat mass. Baseline fat mass, fat-free mass, and daily energy intake were significant predictors of future body weight for both sexes (P<0.0001). Baseline fat mass was a significant predictor of future body fat (P<0.0001). Conclusions: Both males and females have large variations in fat mass, and this variability increases over time, while that of fat-free mass remains relatively stable. Sex differences exist in HFD responses and multivariate predicting models of body weight.