OBJECTIVES: Determine the cost-effectiveness of small intestinal submucosa extracellular matrix (SISEM) relative to standard of care (SC) on wound closure for the treatment of mixed arterial/venous (A/V) or venous (VLUs) leg ulcers.   METHODS: A 2-stage Markov model was used to predict the expected costs and outcomes of wound closure for SISEM and SC. Outcome data used in the analysis were taken from an 8-week randomized clinical trial that directly compared SISEM and SC. Patients were followed for 6 months to assess wound closure. Forty-eight patients completed the study; 25 for SISEM and 23 for SC. SC was defined as a standard moist wound dressing. Transition probabilities for the Markov states were estimated from the clinical trial. The economic outcome of interest was direct cost per ulcer-free week. Resource utilization was based on the treatment regimen used in the clinical trial. Costs were derived from standard cost references. The payer’s perspective was taken.  RESULTS: SISEM-treated wounds healed, on average, after 5.4 weeks of treatment, compared to 8.3 weeks for SC wounds (p=0.02). Furthermore, complete wound closure was significantly higher for patients treated with SISEM (p<0.05), with 20 wounds closed in the SISEM group (80%) and 15 wounds closed in the SC group (65%). After 6 months, patients treated with SISEM had substantially higher ulcer-free weeks compared to SC (20.0 versus 16.8, respectively). Expected direct costs per patient were $2,360 for SISEM and $1,326 for SC. The incremental cost-effectiveness ratio (ICER) for SISEM was $349 (approximately $50/day), indicating that for each $349 paid for SISEM therapy patients gained one additional ulcer-free week.  CONCLUSIONS: SISEM yielded better outcomes at a slightly higher cost in patients with mixed A/V and VLUs. SISEM is an effective treatment for wound healing and should be considered for use in the management of mixed A/V and VLUs.