In some recent trials high dose of Dexamethasone (Dexa) combined with chemotherapy has been used for induction therapy in adults with ALL because it may exert higher antileukemic activity. Increased level of drug in the cerebrospinal fluid might also prevent meningeal leukemic infiltration. However, high dose of Dexa may be associated with an increased risk of sepsis and fungal infections. By using a lower dose of dexamethasone these serious infections may be circumvented without jeopardize the antileukemic activity. The main aim of the EORTC ALL-4 study was to determine the efficacy and toxicity of a lower dose of Dexa administered during the induction therapy, as vs the ones of conventional dose of prednisone (Pred). In the ALL-4 study, patients (pts) ≤ 60 years had to receive either dexamethasone (10 mg/m2/day) or 6-methyl-prednisolone (60 mg/m2/day) on days 1–8 and 15–22 with standard induction chemotherapy (cyclophosphamide i.v. 750 mg/m2 on day 1 and 8; daunorubicine 30 mg/m2 on day 1–3 and 15–16; vincristine 1.4 mg/m2 (maximum 2 mg) and methotrexate /MTX/ i.t. 15 mg on days 1, 8, 15 and 22). All pts than receive the HAM consolidation course (HD-AraC 3 g/m2 every 12 hours on days 1–4; mitoxantrone 10 mg/m2 on days 5–7 and MTX 15 mg i.t. on day 1). Pts in CR received two courses of MA consolidation (MTX 1.5 g/m2 i.v on day 1 and L-asparaginase 104 IU/m2 on day 2). All pts with a family donor were assigned to undergo allo-SCT. Pts without the donor were randomized either to receive autologous stem cells from peripheral blood or continuous standard high maintenance chemotherapy. After a median follow-up of 4.9 years, 198 pts died. Between 1996 and 2003 a total of 325 pts were randomized in the ALL-4 study: 163 in the Dexa arm and 162 in the Pred arm. CR after induction/HAM was achieved in 128 (78.5%) pts receiving Dexa and in 120 (74.1%) pts treated with Pred. Among them, in Dexa group 61 pts relapsed, 19 died in CR and 48 are still in CCR, whereas in the Pred group, 58 pts relapsed, 8 died in CR and 54 are in CCR. The 5-year DFS rates was 32.7% in the Dexa group vs. 34% in the Pred group, the HR=1.15, 95% CI 0.83–1.59, p=0.40. The relapse rates were extremely similar (HR=0.99, p=0.96), whereas the death in CR rate was higher in the Dexa group compared to Pred group: HR=2.33, 95% CI 1.02–5.33, p=0.04. The overall 5-year survival rate in Dexa vs Pred group was 30.7% and 32.5% respectively (HR=1.11, 95% CI 0.84–1.43, p=0.46). The incidence of infection was similar during induction (Dexa: 55% vs Pred: 59%) and during HAM consolidation (Dexa: 85% vs Pred: 78%). More pts were allografted in CR1 in the Dexa than in the Pred arm (45 vs 33), and the mortality post allo-SCT was higher in the Dexa group (12/45=26.7%) than in the Pred group (5/33=15.2%). The results of ALL-4 trial indicate that there is no benefit of dexamethasone compared to 6-methyl prednisone during induction therapy in adult ALL-NHL pts.