Venous thromboembolism (VTE) is often accompanied by co-morbidities, which complicate and confound data interpretation concerning VTE-related mortality, costs and quality of life. We aimed to assess the contribution of co-morbidities to the burden of VTE. The PREFER in VTE registry, across seven European countries, documented and followed acute VTE patients over 12 months. Patients with co-morbidities were grouped in major co-morbidity groups: cancer, cardiovascular (CV) comorbidity (other than VTE), CV risks, venous, renal, liver, respiratory, bone and joint diseases, and lower extremity paralysis. Mortality rates and health-related quality of life (HrQoL) utility values grouped per co-morbidity were compared to the UK general population. Regression analyses were performed to determine the impact of co-morbidities on mortality and HrQoL. VTE were analyzed together and separately as pulmonary embolism (PE) and deep vein thrombosis (DVT). In total, 3455 patients were included, 40.5% with PE and 59.5% with DVT. 13% and 16% of the PE and DVT patients had no co-morbidities and had a 12-month mortality rate of 1.8% and 1.7%, respectively. Frequency and severity of co-morbidities increased mortality rates up to 30%. The EQ-5D-5L index in patients without co-morbidities were 0.826 and 0.838 for PE and DVT. These scores decreased to 0.638 and 0.555 in the presence of co-morbidities. Co-morbidities in VTE patients are common. VTE had an impact on mortality and HrQoL, and additional impact of co-morbidities was seen. Awareness of the presence of co-morbidities is important when making VTE-related treatment decisions. The presence of co-morbidities in PE and DVT patients is common and their frequency and severity in VTE patients have a substantial impact on mortality rates and HrQoL. When adjusting for co-morbidities, the impact of VTE on mortality as well as health-related quality of life remains present. Assessing patients without consideration of co-morbidities might lead to misinterpretations of the disease burden of PE and DVT.