Little is known about the risk of thrombolysis in patients with malignancy, because these patients have been excluded from most clinical trials. We reviewed our acute ischemic stroke (AIS) database for clinical outcomes and complications in patients with current malignancy (CM) who received thrombolytic therapy. Consecutive AIS patients receiving thrombolysis between January 2003 and December 2006 were retrospectively abstracted in accordance with the American Stroke Association's Get With the Guidelines-Stroke definitions and charts were reviewed for history of malignancy. Patients with brain metastases did not receive tissue plasminogen activator (tPA). Stepwise logistic regression was used to identify independent predictors of in-hospital mortality. Of 308 AIS patients treated with thrombolytic therapy, 210 (68%) received intravenous (IV) tPA only, 41 (13%) received IV tPA plus intra-arterial therapy (IAT), and 57 (18%) received IAT only. Eighteen patients (5.8%) had a CM, and 26 patients (8.4%) had a remote history of malignancy. Patients with CM had a higher in-hospital mortality (38.9% vs 19.7 %; P=.05) and were more likely to have died due to worsening medical comorbidity (71.4% vs 9.6%; P < .001). The rate of symptomatic intracranial hemorrhage (ICH) was similar in the 2 groups (5.6% vs 2.7%; P=.47). In multivariate analysis, the only independent predictors of mortality were National Institutes of Health Stroke Scale score, history of hypertension, and smoking. CM was not independently associated with increased in-hospital mortality following thrombolysis. Mortality was attributable largely to medical comorbidities, not to symptomatic ICH. Our data suggest that thrombolysis may be a reasonable option for patients with malignancy who have acceptable medical comorbidities and performance status. Further research is warranted.