Since its recognition in the early 1980s, enteric septicemia of catfish (ESC), caused by the gram-negative enteric Edwardsiella ictaluri, is one of the most significant pathogens affecting catfish aquaculture. In efforts to improve disease management in U.S. catfish aquaculture, a live-attenuated ESC vaccine and method of in-pond oral vaccine delivery was developed. This work evaluated the efficacy of the oral delivery platform using a live-attenuated E. ictaluri vaccine under simulated commercial conditions. Channel catfish fingerlings were orally vaccinated approximately 40-50 days poststocking by mixing the attenuated vaccine with feed using a patent-pending mechanized delivery system. Across three discrete years under varying evaluation methods, vaccination resulted in significant improvements in survival, feed conversion ratio, feed fed, and total yield. An economic analysis of experimental data suggests a significant positive net economic benefit from vaccination.After accounting for a projected cost of vaccination, the realized improvements in survival and yield resulted in an estimated benefit exceeding $3,500/ha ($1,400/acre) on fingerling operations. These results suggest vaccinating channel catfish fingerlings against ESC is an effective strategy to mitigate ESC-related losses and can significantly improve production efficiency and profitability on catfish operations.