Guidelines for the treatment of venous thromboembolism (VTE) are mainly based on randomized controlled trials, but a number of patients with VTE are excluded from trials due to co-morbidities (i.e., recent bleeding, renal insufficiency, thrombocytopenia, abnormal prothrombin time or pregnancy). Thus, treatment regimens derived from clinical studies may not be suitable for all patient groups. RIETE (Registro Informatizado de la EnfermedadTromboEmbólica) is a Spanish registry of consecutively enrolled patients with objectively confirmed, symptomatic acute VTE. We compared the clinical outcome during the first 3 months of therapy of VTE patients with at least one of the mentioned co-morbidities with that in patients without them. Of 6855 patients enrolled up to February 2004, 1635 (24%) had at least one reason to be excluded from clinical trials: recent bleeding (2.6%); renal insufficiency (13.6%); thrombocytopenia (2.5%); abnormal prothrombin time (9.1%) and pregnancy (0.7%). During the 3-month follow-up period the rates of fatal pulmonary embolism (odds ratio: 3.3; 95% CI: 2.5-5.2); minor bleeding (odds ratio: 1.8; 95% CI: 1.3-2.2); major bleeding (odds ratio: 3.1; 95% CI: 2.3-4.1) and fatal bleeding (odds ratio: 4.1; 95% CI: 2.1-8.0) were significantly higher in patients with at least one of these co-morbidities than in the remaining 5220 patients. The clinical outcome was significantly worse inpatients with either recent bleeding, renal insufficiency, thrombocytopenia, abnormal prothrombin time, or pregnancy. The expanding RIETE database of "real-world"outcomes may lead to improved treatment of VTE, especially for those patients not usually included in randomized clinical trials.