Fifty consecutive episodes of septicemia were studied in 41 children who had acute lymphoblastic leukemia. Seventy-six percent of these episodes occurred when the absolute granulocyte count was 200/mm3 or less and were caused by gram-negative enteric and gram-positive mucocutaneous bacteria. In eight patients, Streptococcus pyogenes was isolated at the time when ALL was diagnosed. Multiple anaerobic and aerobic isolates from a single blood culture were associated with abdominal distress, whereas Streptococcus pneumoniae and Hemophilus influenzae septicemia occurred in associated with respiratory illnesses. When patients with severe compromise of anatomic barriers or respiratory disease were excluded, 94% of all patients with septicemia had an AGC of less than 200/mm3. The data provide guidelines for treatment for febrile patients with ALL based upon the AGC, the phase of the disease, and on the presence of associated respiratory or abdominal findings.