Infants with acute lymphoblastic leukemia have a poor prognosis. The Children's Cancer Group (CCG) 1953 protocol tested the hypothesis that intensification of therapy would improve outcome for these patients. This intensified therapy resulted in better disease control, but resulted in greater toxicity. In this paper, we report the infectious complications associated with this intensified therapy. We retrospectively analyzed the infectious complications reported on the case report forms of all 115 patients enrolled on CCG 1953. Overall 495 infectious complications were identified in 115 patients. Bacterial infections occurred most frequently (74%), followed by viral (13%), fungal (11%), and protozoan (1%). Infection related mortality disproportionately occurred with viral (31%) and fungal (19%) infections. Twenty-three percent (n=26) of patients died of infectious complications, with the majority occurring during induction/intensification. Lower respiratory infections contributed to death in 12 patients and were most commonly viral (n=6) and fungal (n=3). Intensification of therapy resulted in increased infectious complications and deaths compared with previous studies. Future studies will need to focus on: (1) decreasing intensification during the first month of therapy, (2) developing targeted therapies, and (3) improving measures designed to prevent, quickly diagnose, and appropriately treat infections.