Abstract: Background: Mixtures of herbicide sites of action (SOA) are often promoted as an effective practice for proactive herbicide resistance management, but the cost of implementation is less-often considered in these recommendations, especially in the academic literature. Objective: Estimate the costs of implementing herbicide SOA mixtures that are effective for herbicide resistance management under different scenarios involving crops, weed species, and existing resistance. Methods: Using data from the Guide for Weed, Disease, and Insect Management in Nebraska, an optimization function was used to find the lowest cost for effective weed control (single herbicide providing ≥90%), and effective resistance management (at least 2 SOA providing ≥90%) under various crop, weed, and herbicide resistance scenarios. Results: In corn and soybean, effective SOA mixtures for waterhemp and Palmer amaranth increased herbicide costs at least 2-fold compared to herbicide costs that provided effective weed control with a single SOA. Resistance to certain SOA had greater impact on the cost of effective herbicide mixtures; in corn, resistance to SOA Group 5 or Group 9 herbicides caused the greatest increase in mixture costs, whereas in soybean Group 9 or Group 14 resistance caused the greatest increase in mixture costs. In dry edible bean, effective mixtures were at least 5 times more expensive than similar scenarios in soybean, and in several scenarios, there were no herbicide mixtures available that met effective resistance management criteria. Conclusions: The use of effective herbicide SOA mixtures has sound scientific basis for slowing the evolution of herbicide resistance, but the cost of implementation is a major barrier for widespread adoption even in fields where herbicide resistance is not yet present.