Four centers participated in a double-blind study in which 53 patients with angiographically documented acute massive pulmonary embolism (baseline Miller index > or = 17/34 and mean pulmonary artery pressure > or = 20 mm Hg) were randomly assigned to treatment with either 0.6 mg/kg bolus injection of alteplase over 15 min with a maximum dose of 50 mg (bolus group; n = 36), or 100 mg of alteplase over 2 h (2-h group; n = 17). The primary objective was to compare the rapidity of resolution of pulmonary embolism as judged by the change in total pulmonary resistance (TPR) over the initial first hour. Further objectives were to evaluate the changes in TPR over the next 11 h and the degree of lung scan resolution at 20 to 28 h. At 1 h, TPR decreased by 29 +/- 17 percent in the bolus group and by 36 +/- 16 percent in the 2-h group (mean +/- SD; p = 0.19). Continuous monitoring of TPR revealed that this variable improved in both groups without significant intergroup differences over the 12-h study period, although TPR decreased initially faster in the 2-h group. At 20 to 28 h, the absolute improvements in the lung scan perfusion defect were 14 +/- 12 percent in the bolus group compared with 13 +/- 9 percent in the 2-h group, with no significant intergroup differences. Major bleeding occurred in one patient of the 2-h group (6 percent) and in three patients of the bolus group (8 percent) (p > 0.5). Four patients (three from the bolus group and one from the 2-h group) may have experienced recurrent pulmonary embolism during the hospital stay. Neither death nor intracranial bleeding occurred.