Obesity predicted decreased EFS in pediatric ALL (ASH 2004, Abstract#992). Here we report the effect of obesity, defined as body mass index >30, in 906 adults enrolled in two GIMEMA trials. The first study (1996–2001) included 45 obese (9.5%) and 426 non-obese patients. Obese patients were older, received lower total doses of vincristine (VCR) and daunomicin (DNR) and had more hepatic and pulmonary toxicity during induction than not-obese patients; the incidence of toxic deaths and complete remissions (CR) were similar. By multivariate analysis, obesity, high WBC, age >30y and presence of BCR-ABL at diagnosis independently predicted EFS. Hazard ratios (HR) for any events were respectively 1.506 (1.059–2.142, p=0.0228), 1.002 (1.001–1.003, p=0.0022)), 1.015 (1.006–1.025, p=0.0014) and 1.8 (1.4–2.4, p<0.0001). The effect of obesity on EFS was present across all levels of WBC, but was observed prevalently in BCR-ABL-negative patients. 3y-EFS in obese vs non-obese patients was 22.9% vs 39.5% (p=0.0064) in BCR-ABL negative patients and not significantly different (14% vs 22%, p=0.77 n.s.) in BCR-ABL positive patients. These results were verified in the following study started in 2000, which included 50 obese (11%) and 385 non-obese patients. In this study, obese patients received 28% and 21% less than the planned doses of VCR and DNR respectively; also they were more likely than non-obese patients to be >30 y of age and BCR-ABL-positive. The incidence of toxicity, toxic deaths and CR were similar in obese and non-obese patients. In the BCR-ABL negative patients, obesity tended to predict EFS. 2y-EFS was 26.6% in the obese and 49.4% in the non-obese patients (p=0.067). By multivariate analysis HR for any events of obesity, WBC>50 and age>30 were respectively 1.53 (0.92–2.58, p=0.107), 1.64 (1.12–2.39, p=0.012) and 1.74 (1.19–2.54, p=0.004). In conclusion, obesity seems associated with a poorer EFS in patients with BCR-ABL negative ALL; this might be caused by the lower doses of chemotherapy obese patients receive. Studies aimed to clarify chemotherapy pharmacokinetics, toxicity and efficacy in obese patients are warranted.