Inbred C57BL/6J mice displayed large individual variations in weight gain when fed a high-fat diet (HFD). The objective of this study was to examine whether this predominantly nongenetic variability could be predicted by relevant baseline features and to explore whether variations in these significant features were influenced during pregnancy and/or lactation. Fat mass (FM), fat-free mass (FFM), food intake (FI), resting metabolic rate (RMR), physical activity (PA), and body temperature (T(b)) were all evaluated at baseline in 60 mice (aged 10-12 weeks) before HFD feeding. Regression analyses showed that baseline FM was a strong positive predictor of weight gain between 4 and 16 weeks of HFD. Baseline PA was negatively associated with weight gain at week 8, 12, and 16, and baseline FFM had a positive effect at week 12 and 16. In a second experiment, 40 female mice were mated and litter sizes (LS) were manipulated on day 3 of lactation. Weaning weight and postweaning growth rate (GR) had positive impacts on FM and FFM at age 9 weeks (FM, P = 0.001; FFM, P < 0.001: n = 97). Lactation LS had a negative effect on weaning weight and a positive effect on postweaning GR. In conclusion, our results show that obesity induced by HFD was associated with a higher baseline FM, a higher baseline FFM and a lower baseline PA level before the exposure of HFD. Two of these traits (FM and FFM) were influenced by lactation LS via weaning weight and postweaning GR.