We investigated whether serum from normal weight women is less mitogenic and more apoptotic than sera from the same women in the overweight state. Sera from premenopausal women, age (mean ± SEE) 34.6 ± 0.53 years, who were randomized to caloric restriction (CR) (n = 13), CR + aerobic exercise (AE) (n = 14), or CR + resistance training (RT) (n = 20) were used to culture endometrial cancer cells. Phases of the cell cycle were determined, and proliferating cell nuclear antigen (PCNA) positivity was used to assess proliferation and apoptosis was assessed by determining cleaved caspase-3 and poly-ADP-ribose polymerase (PARP). Analyses showed that overall, cells grown in sera from the weight-reduced state had significantly more cells in G0/G1 and significantly fewer cells in the S and G2/M phases of the cell cycle than cells grown in sera from the overweight state. PCNA staining confirmed that cells grown in sera from the weight-reduced state had fewer proliferating cells. Cleaved caspase-3 and PARP were not different in cells grown in sera from the weight-reduced state compared to the overweight state. We conclude that weight loss with or without exercise could lower the risk for cancer through changes in serum that result in reduced cellular mitogenicity.