With an aging population venous ulceration is likely to become an increasing problem. Despite improvements in care and the widespread introduction of compression bandaging, the mainstay of current management, a significant proportion of venous leg ulcers remain hard to heal. Therefore, a single-blinded, randomized multicenter study was performed to compare wound size reduction using amelogenin proteins (Xelma) formulated into a solution which forms a temporary extracellular matrix on contact with the wound bed. Propylene glycol alginate 7% served as a control. Patients were randomized to receive either amelogenin protein or control treatment. The investigational products were applied weekly under soft silicone secondary dressings for up to a maximum of 12 weeks. Compression therapy was maintained throughout the investigation. Wound size reduction was measured by tracing and all wounds were photographed. In total 123 patients were recruited, 62 patients in the amelogenin group, and 61 in the control group, respectively. Subgroup analyses were performed for ulcers with a size>10 cm2 at baseline and for ulcers of duration of >12 months. The wound size reduction was greatest in the group treated with amelogenin (33.8 vs. 25.6%, n=117), this difference being greatest for larger ulcers (25 vs. 7.9% for ulcers>10 cm(2), n=61) and those of long duration (29.3 vs. 10.9% for ulcers>12-month duration, n=61). We conclude that this product may be clinically useful in the treatment of these venous leg ulcers.