The natural history of patients with venous thromboembolism (VTE) who develop a major bleeding complication while on anticoagulant therapy is not well known. RIETE is a prospective registry of consecutive patients with symptomatic, objectively confirmed, acute VTE. The clinical characteristics, treatment decisions and outcome of all VTE patients who had major bleeding during the first three months of anticoagulant therapy were retrospectively studied. As of January 2007, 17, 368 patients were included in RIETE. Of these, 407 (2.3%) had major bleeding during the study period: 144 gastrointestinal, 119 haematoma, 51 intracranial, 43 genitourinary, 50 other. In 286 (69%) patients anticoagulant therapy was discontinued, in 74 (18%) not modified, in 38 (9.1%) a vena cava filter was inserted. During the first 30 days after bleeding, 24 (5.9%) patients re-bled, 20 (4.9%) had recurrent VTE, 133 (33%) died. Of these, 75 died of bleeding, 12 of recurrent pulmonary embolism. Most deaths occurred shortly after the bleeding episode (median: 1 day). On multivariate analysis, insertion of a vena cava filter was the only variable independently associated with a lower incidence of fatal bleeding (odds ratio [OR]: 0.10; 95% confidence interval [CI]: 0.01-0.79) and all-cause mortality (OR: 0.21; 95% CI: 0.07-0.63). In conclusion, the occurrence of major bleeding in patients with VTE is outstanding in terms of overall mortality (33% within 30 days), fatal bleeding (18%) or re-bleeding (5.9%). However, these patients also have an increased incidence of recurrent VTE (4.9%) and fatal pulmonary embolism (1.2%).