OBJECTIVE: Acute lymphoblastic leukemia (ALL) among children may be a rare outcome of a delayed non-specific infection in situations of overall low herd immunity. We evaluated the hypothesis as to whether newly diagnosed ALL cases, compared to their controls, are characterized by lower herd immunity, as reflected in a more seronegative spectrum to several agents, with the exception of a strongly positive response to a single infectious agent, assumed to trigger ALL. METHODS: The study included 94 incident cases of ALL, from all pediatric hematology-oncology units of Greece, and 94, matched for age and gender, controls hospitalized with minor non-infectious conditions. The past exposure to common infections was assessed using 10 serological markers. RESULTS: There was little evidence for an association of ALL with the serology of any of the studied infectious agents among the very young children. In contrast, among children aged 5 years or older, leukemia was inversely associated with seropositivity to Epstein-Barr virus, human herpes virus-6, Mycoplasma pneumoniae and parvovirus B19. CONCLUSIONS: Among children aged 5 years or older the risk of leukemia may be higher when the low herd immunity for several agents is challenged by late infection from an agent that, as a rule, would attack children at a younger age.