OBJECTIVES: To determine the comparative cost-effectiveness of three commercially available cellular engineered skin substitutes used in the treatment of venous leg ulcers (VLU). METHODS: A Markov simulation model was developed to compare the one year direct costs and outcomes of a porcine small intestinal submucosa (SIS) wound matrix to fibroblast-derived (FSS) and fibroblast/keratinocyte-derived (FKSS) cellular and/or tissue-derived products (CTDP) used in the treatment of chronic VLUs. The model used three health states: a chronic ulcer, a healed ulcer and death. To predict clinical and economic outcomes a systematic literature search was conducted to identify 1) comparative chronic VLU clinical trials that reported healing/recurrence outcomes for the three skin substitutes, and 2) economic studies reporting VLU treatments and resource utilization. The effectiveness of the products was assumed equal to that reported in four clinical trials identified in the literature. Ulcer-free weeks were used as the measure of clinical effectiveness. Direct costs of treatment were derived from Medicare-allowable costs and economic studies identified in the literature which included costs associated with hospitalization, home health care, ambulatory clinic visits, CTDP products, drugs, compression stockings and other resources associated with VLU care. The payer perspective was taken in the analysis and sensitivity analyses were performed to assess model uncertainty. RESULTS: SIS was the economically dominant therapy compared to FKSS and FSS with a comparative effectiveness ratio of $215 per ulcer-free week versus $367 and $409, respectively. Relative to SIS, the incremental cost-effectiveness ratio (ICER) for FKSS was $1609 while the ICER for FSS was $1132. SIS remained the least costly alternative per ulcer-free week across all sensitivity analyses.  CONCLUSIONS: When cellular and/or tissue-derived products are needed for chronic VLU therapy our results indicate that SIS is the most cost-effective choice between the three commercially available alternatives analyzed.