Polymorphic genes have been linked to the risk of acute lymphoblastic leukemia (ALL). Surrogate markers for a low burden of early childhood infections are also related to increased risk for developing childhood ALL. It remains uncertain, whether siblings of children with ALL have an increased risk of developing ALL. This international collaboration identified 54 sibships with two (N=51) or more (N=3) cases of childhood ALL (ages <18 years). The 5-year event-free survival for 61 patients diagnosed after 1 January 1990 was 0.83±0.05. Ages at diagnosis (Spearman correlation coefficient, r S=0.41, P=0.002) were significantly correlated, but not WBCs (r S=0.23, P=0.11). In 18 sibships with successful karyotyping in both cases, six were concordant for high-hyperdiploidy (N=3), t(12;21) [ETV6/RUNX1] (N=1), MLL rearrangement (N=1) or t(1;19)(q23/p13) (N=1). Eleven sibships were ALL-subtype concordant, being T-cell ALL (T-ALL) (N=5, of a total of six sibships, where the first-born had T-ALL) or B-lineage ALL belonging to the same cytogenetic subset (N=6), a finding that differs significantly from the expected chance distribution (κ: 0.58; P<0.0001). These data indicate strong genetic and/or environmental risk factors for childhood ALL that are restricted to specific ALL subtypes, which must be taken into account, when performing epidemiological studies to reveal etiological factors.