Bloom’s syndrome is a rare human autosomal recessive disorder which combines a marked genetic instability and an increased risk of developing all types of cancers, and which results from mutations in both copies of the BLM gene encoding a RecQ 3’-5’ DNA helicase. We recently showed that BLM is phosphorylated and excluded from the nuclear matrix during mitosis. We now show that the phosphorylated mitotic BLM protein is associated with a 3’-5’ DNA helicase activity, and interacts with topoisomerase IIIa. We demonstrate that in mitosis-arrested cells, ionizing radiation and roscovitine treatment both result in the reversion of BLM phosphorylation, suggesting that BLM could be dephosphorylated through the inhibition of cdc2 kinase inhibition. This was further supported by our data showing that cdc2 kinase activity is inhibited in g-irradiated mitotic cells. Finally we show that following ionizing radiation, BLM is not involved in the establishment of the mitotic DNA damage checkpoint, but is subjected to a subcellular compartment change. These findings lead us to propose that BLM may be phosphorylated during mitosis, probably through the cdc2 pathway, to form a pool of rapidly available active protein. Inhibition of cdc2 kinase following ionizing radiation would lead to BLM dephosphorylation and possibly to BLM recruitment to some specific sites for repair.