Mutations in the BLM gene cause human Bloom syndrome (BS), an autosomal recessive disorder of growth retardation, immunodeficiency and cancer predisposition. Homozygous null Blmm3/m3 mice are cancer prone with a 5-fold increased risk of cancer compared with Blmm3/+ and Blm+/+ mice. Irradiation of Blmm3/m3 mice increased the risk to 28-fold. Tumors occurred mainly in the hematopoietic system and were similar to those in BS based on detailed histologic and immunohistochemical analyses. Irradiated Blm-deficient mice thus provide a novel model for understanding accelerated malignancies in BS and a new platform for investigating the molecular basis for a wide range of hematopoietic neoplasms.