We investigated the efficacy and safety of extended enoxaparin monotherapy in symptomatic patients with acute pulmonary embolism (PE). We randomized 40 patients in a 1:1 allocation to enoxaparin monotherapy (1 mg/kg twice daily for 10-18 days, and then 1.5mg/kg once daily until day 90) (n = 20) or to enoxaparin 1.0 mg/kg twice daily as a bridge to warfarin with a target international normalized ratio of 2.0-3.0 for 90 days (at least 10 doses of enoxaparin overlapping with warfarin for at least 4 days) (n = 20). All patients underwent echocardiography, cardiac troponin I (TnI), and brain natriuretic peptide testing to identify patients with an increased likelihood of adverse clinical outcomes. The end-points were newly diagnosed deep venous thrombosis (DVT) or PE and bleeding events through day 90. In 15 patients on extended enoxaparin therapy, we used repeated measure analysis of variance (ANOVA) to investigate differences in anti-Xa levels obtained at 2, 4, 8 and 12 weeks. The patients' mean age was 52 +/- 17 years; the most common comorbidities were obesity (58%), hypertension (30%), concomitant DVT (30%) and cancer (15%). Twelve (30%) patients had elevated cardiac Tnl >0.1 mg/l and 11 (28%) had moderate or severe right ventricular dysfunction on echocardiography. Ten (25%) patients received thrombolysis with a continuous infusion of 100 mg alteplase prior to randomization. During a 90-day follow-up, one patient from the enoxaparin monotherapy group suffered symptomatic distal DVT; one from the warfarin group had recurrent symptomatic PE (p = 1.0). None of the study patients had major hemorrhage; two warfarin group patients had minor bleeding compared with none in the enoxaparin monotherapy group (p = 0.49). Repeated measure ANOVA did not reveal significant differences in anti-Xa levels over time (p = 0.217). In patients with acute symptomatic PE, extended enoxaparin monotherapy is feasible and warrants further investigation in a large clinical trial.