Mixed arterial/venous (A/V) ulcers are difficult to treat and slow to heal likely as a result of deficiencies in molecular and cellular elements in the wound bed. Recently, biomaterials have been developed that replace extracellular matrix (ECM) molecules and growth factors critical to the normal healing process. In this study, the effects of OASIS and Hyaloskin were evaluated to compare the effectiveness of these two ECM-based products in their ability to achieve complete wound healing of mixed A/V ulcers. After 16 weeks of treatment, patients in each group were evaluated on four criteria: complete wound healing, time to dressing change, pain and comfort. Complete wound closure was achieved in 82.6% of OASIS-treated ulcers compared with 46.2% of Hyaloskin-treated ulcers (P < 0.001). Statistically significant differences favouring the OASIS treatment group were also reported for time to dressing change (P < 0.05), pain (P < 0.05) and patient comfort (P < 0.01). Overall, OASIS was superior to Hyaloskin for the treatment of patients with mixed A/V ulcers, a population in which standard treatment options largely consist of moist wound dressings and compression therapy is typically not an option. OASIS is a useful and well-tolerated treatment for mixed A/V ulcers that has the potential to improve quality of life and reduce costs associated with standard of care.