Children with acute lymphoblastic leukaemia (ALL) typically gain weight at excessive rates during and after therapy, and a high proportion of young adult survivors are obese. Previous studies have failed to identify the abnormalities in energy balance that predispose these children to obesity. The aim of this study was to determine the cause of excess weight gain in children treated for ALL by testing the hypothesis that energy expenditure is reduced in these patients. Twenty children [9 boys, 11 girls; mean age 10.9 (3.2) y] treated for ALL who had shown excess weight gain, but were not obese [mean body mass index SD score 0.70 (1.04)], were closely and individually matched with 20 healthy control children [9 boys, 11 girls; mean age 10.7 (3.0) y; mean body mass index SD score 0.27 (0.91)]. In each child we measured total energy expenditure by doubly-labeled water method, resting energy expenditure, energy expended on habitual physical activity, and energy intake. Total energy expenditure was significantly higher in control subjects than in patients: mean paired difference 1185 kJ/d (282 kcal/d), 95% confidence interval (CI) 218-2152. This difference was largely due to reduced energy expended on habitual physical activity in the patients. Resting energy expenditure was lower in the patients: mean paired difference 321 kJ/d (76 kcal/d), 95% CI 100-541. Energy intake was also lower in the patients: mean paired difference 1001 kJ/d (238 kcal/d), 95% CI 93-1909. Children treated for ALL are predisposed to excess weight gain, and subsequently obesity, by reduced total energy expenditure secondary to reduced habitual physical activity. Prevention of obesity in ALL should focus on modest increases in habitual physical activity, modest restriction of dietary intake, and monitoring of excess weight gain.