Introduction. Health care policy decision makers seek the highest quality products at the lowest cost for their patients. Cost-benefit analysis is a helpful tool and can be used together with other sources of information to ensure the most efficient use of medical resources. Objective. The objective of this retrospective comparative cohort study is to evaluate the cost effectiveness of fish skin therapy compared with standard of care (SOC) on chronic diabetic foot ulcers (DFUs). Methods. Retrospective patient data collected in a single wound care setting from 2014 to 2017 were included. In total, 59 DFUs treated with fish skin were used to calculate transition probabilities for a Markov model in which a hypothetical patient cohort treated with fish skin was compared with an identical hypothetical patient cohort treated with SOC. Cost was from the perspective of the payer, and the time horizon was set at 1 year. Results. The model indicated that fish skin treatment could result in lower costs ($11 210 vs. $15 075 per wound), more wounds healing (83.2% vs. 63.4%), fewer amputations (4.6% vs. 6.9%), and a higher quality of life (0.676 vs. 0.605 quality-adjusted life year [QALY]) than the SOC. A probabilistic sensitivity analysis, based on a Monte Carlo simulation, indicated that the fish skin treatment (on DFUs) would be 93.6% likely to be cost effective for a willingness to pay at $100 000 per QALY and 71.4% likely to be cheaper than SOC. Conclusions. Including fish skin grafts in the SOC for DFU treatment has the potential to reduce costs while improving patient outcomes.