One hundred-sixty-four ALL patients were compared to 545 controls for differences in phenotype and gene frequencies at the Properdin factor B locus. In addition, 90 of the ALL patients were immune phenotyped. A significant association with the Bf F allele and ALL was found, resulting in an estimated relative risk of 3.62. There was no difference in the Bf S phenotype between ALL patients and controls. However, those homozygous for the Bf S allele are at a significantly low risk of 0.30 for developing ALL. ALL patients with a non-B/T cell type were 2.5 times more likely to be Bf SS homozygotes; in contrast, those patients with the pre-B cell type were 2.5 more likely to be Bf FF homozygotes. These data suggest association of the Bf locus with an ALL protection and/or susceptibility gene(s).