In order to elucidate the natural history of upper extremity deep venous thrombosis (UEDVT), we compared the morbidity and mortality of patients with UEDVT and that of patients with both UEDVT and lower extremity deep venous thrombosis (LEDVT). Between 1993 and 1996, 21 patients presented to our institution with both LEDVT and UEDVT (Group 1). During the same time period, 144 patients were diagnosed with UEDVT alone (Group 2). The diagnosis was confirmed by duplex scanning in all patients. In Group 1, there were 14 females (67%) and 7 males (23%) with ages ranging from 25 to 97 yr old [mean 73 yr old +/-17 yr (SD)]. In Group 2, there were 84 females (58%) and 60 males (42%) with ages ranging from 9 to 101 yr old [mean 67 yr old +/-17 yr (SD)]. Differences in age and sex between the two groups were not statistically significant. In Group 1, systemic anticoagulation was implemented in 17 patients (81%). Two patients (9.5%) required placement of a SVC and IVC filters due to contraindication to anticoagulation. One patient did not receive anticoagulation, and one patient was only started on aspirin. In Group 2, treatment consisted of systemic anticoagulation in 94 patients (65%). The remainder of the patients were treated with aspirin in three patients (2%) or no anticoagulation in 31 patients (19%). Sixteen patients (11%) underwent placement of a SVC filter either due to failure of anticoagulation to prevent pulmonary embolism (two patients) or contraindication to anticoagulation (14 patients). Pulmonary emboli were documented by ventilation/perfusion lung scan in two patients (9.5%) in Group 1 and in 16 patients (11%) in Group 2. In the first group, 8 of the 21 patients (38%) were dead within 1 month of the diagnosis of UEDVT, and 11 of 21 patients (52%) were dead within 2 months of the diagnosis of UEDVT. In the second group, 20 of 144 patients (14%) were dead within 1 month of the diagnosis of UEDVT and 38 of 144 patients (26%) were dead within 2 months of diagnosis (P<0.02). Our data suggest that patients with both UEDVT and LEDVT have a higher mortality than patients with UEDVT alone. As the risk for pulmonary embolism is similar in both groups, we speculate that the severity of medical illness in patients with both UEDVT and LEDVT may contribute to the higher mortality. This is the first study to examine the mortality of this group of patients.