The p66Shc gerontogene may affect healthspan by promoting fat accumulation. We assessed changes of p66Shc-mRNA in peripheral tissues in relation to maternal obesity and the moderating effects of resistance-training (RT) exercise in elderly frail women. Thirty-seven women participated in a 4-month RT program. Twenty were offspring of lean/normal weight mothers and 17 were offspring of overweight/obese mothers (OOM). P66Shc was assessed in peripheral blood mononuclear cells (PBMC) and in subcutaneous adipose tissue (SAT) before and after RT. Overall, OOM showed elevated p66Shc mRNA levels in the PBMC. Independently from maternal obesity, following RT there was a decrease in p66Shc expression in PBMC but not in SAT, particularly in subjects with a high body mass index. Results suggest that maternal obesity has long-term effects on the expression of genes involved in mitochondrial function and fat deposition and that RT modifies p66Shc expression in PBMC with greater effects in obese subjects.