Background and Purpose: Reliable predictors of hemorrhagic transformation (HT) after stroke thrombolysis have not been identified. We analyzed hemorrhage in a randomized trial of tissue plasminogen activator (t-PA) vs placebo in ischemic stroke patients. We hypothesized that acute diffusion-weighted imaging (DWI) lesion volumes would be larger and blood pressures would be higher in patients with HT. Methods: HT was assessed 2 to 5 days after treatment in 97 patients. Hemorrhage was assessed by using susceptibility-weighted imaging sequences and was classified as petechial hemorrhagic infarction (HI) or parenchymal hematoma (PH). Results: PH was more frequent in t-PA– (11/49) than in placebo- (4/48) treated patients (P=0.049). Patients with PH had larger DWI lesion volumes (63.1±56.1 mL) than did those without HT (27.6±39.0 mL, P=0.033). There were no differences in baseline systolic blood pressure (SBP) between patients with and without hemorrhage. Weighted average SBP 24 hours after treatment was higher in patients with PH (159.4±18.8 mL, P<0.011) relative to those without HT (143.1±20.0 mL). Multinomial logistic regression indicated that PH was predicted by DWI lesion volume (odds ratio=1.16 per 10 mL; 95% CI, 1.03 to 1.30), atrial fibrillation (odds ratio=9.33; 95% CI, 2.30 to 37.94), and 24-hour weighted average SBP (odds ratio=1.59 per 10 mm Hg; 95% CI, 1.14 to 2.23). Conclusions: Pretreatment DWI lesion volume and postthrombolysis BP are both predictive of HT. Consideration should be given to excluding patients with very large baseline DWI volumes from t-PA therapy and to more stringent BP control after stroke thrombolysis.