Objectives: To investigate the prevalence and potential risk factors of obesity after therapy for childhood acute lymphoblastic leukemia (ALL). Study Design: 39 ALL patients (age 10.7–20.5 years) who were in first remission for 3.4–14.6 years after standardized treatment with chemotherapy plus cranial irradiation (n = 25) or with chemotherapy alone (n = 14) were examined. After fasting overnight, the following parameters were investigated: body mass index (BMI) of patients and their parents; patients’ BMI before ALL therapy; serum free thyroxin, growth hormone-dependent factors, estradiol, testosterone, cortisol, leptin and c-peptide; fat-free mass (bioelectrical impedance); resting metabolic rate (RMR, indirect calorimetry); caloric intake (24-hour recall); and physical activity (questionnaire). RMR data were applied to the fat-free mass and compared with 83 controls. Results: The prevalence of obesity (criterion: BMI > 2 SDS) was significantly (p < 0.05) higher after ALL therapy (38%; irradiated patients 48%, non-irradiated patients 21%) than before therapy (3%). Compared to non-irradiated patients, irradiated patients had significantly lower RMRs (–1.07 ± 0.24 vs. –0.32 ± 0.21 SDS; p < 0.05), reduced physical activity levels (1.41 ± 0.03 vs. 1.52 ± 0.03; p < 0.05), and lower concentrations of insulin-like growth factor-binding protein-3 (–0.65 ± 0.17 vs. 0.25 ± 0.33 SDS; p < 0.05) and of free thyroxin (1.17 ± 0.06 vs. 1.38 ± 0.08 ng/dl; p < 0.05). Caloric intake was adequate. Conclusions: After ALL during childhood, patients face a higher risk of obesity. In the cranially irradiated patients, the likely causes are low physical activity, RMRs and hormonal insufficiency.