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This is a prospective case series study aimed to preliminarily assess the efficacy and safety of a skin substitute (Apligraf) application to heal chronic diabetic foot ulcers (DFUs) in a group of diabetic patients who were treated in the diabetic foot clinic of King Abdulaziz University, Jeddah, Saudi Arabia. Five consecutive patients who presented with large, hard to heal neuropathic ulcer for an average duration of 162.2 weeks were treated with multiple applications of Apligraf and followed up for 40 weeks. Three out of the five ulcers (60%) ended up with complete wound closure. One plantar ulcer healed partially and another plantar ulcer healed after 14 weeks but recurred after 10 weeks of wound closure due to infection. This small case series study indicates the importance of careful patient selection in healing chronic (DFUs) when using a skin substitute like Apligraf. Long standing large plantar ulcer in a non-complaint diabetic patient is the most difficult to heal and this should be kept in mind when using this relatively high cost modality of treatment.