Background: Imatinib mesylate (IM) and other tyrosine kinase inhibitors that inhibit BCR-ABL have revolutionized the treatment of chronic myelogenous leukemia and also improved Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) outcomes. BCR-ABL inhibitors are generally well tolerated, but both IM and dasatinib induce platelet dysfunction, which is of particular concern in the setting of thrombocytopenia in ALL patients. Three Ph+ ALL patients receiving IM in conjunction with systemic and intrathecal (IT) chemotherapy at the University of Maryland Greenebaum Cancer Center (UMGCC) developed subdural hematomas (SDH). We sought to define risk factors for SDH. Methods: Charts were reviewed for SDH risk factors, including thrombocytopenia, coagulopathy, lumbar punctures and meningeal leukemia, and SDH incidence was compared in Ph+ and Ph- ALL patients receiving multi-agent systemic and IT chemotherapy with and without IM, respectively, at UMGCC from 2007 through 2010. Results: Three Ph+ ALL patients developed SDH during treatment courses 1, 3, and 3, respectively. SDH was unilateral in two patients and bilateral in one. All were thrombocytopenic and had undergone repeated lumbar punctures, but none was coagulopathic nor had meningeal leukemia. SDH was treated with burr hole surgery in two patients, and conservatively in one. One patient died of resistant leukemia and one of post-transplant complications, while the third is alive and in remission 26 months after diagnosis and 22 months after SDH. SDH incidence was significantly higher in Ph+ compared to Ph- ALL patients receiving treatment with and without IM, respectively (3 of 10 vs. 0 of 22; p<0.05). Conclusions: Our data suggest that IM is a risk factor for SDH, likely due to IM-induced platelet dysfunction, and that patients with Ph+ ALL receiving IM, and likely dasatinib, in conjunction with systemic and IT chemotherapy may be at increased risk of SDH and should be closely monitored for subtle manifestations of this serious complication.