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Objective Infection following cochlear implantation is medically and economically devastating. The cost-effectiveness (CE) of colonization screening and decolonization for infection prophylaxis in cochlear implantation has not been examined. Study Design An analytic observational study of data collected from purchasing records and the literature. Methods Costs of Staphylococcus aureus colonization screening and decolonization were acquired from purchasing records and the literature. Infection rates after cochlear implantation and average total costs for evaluation and treatment were obtained from a review of the literature. A break-even analysis was performed to determine the required absolute risk reduction (ARR) in infection rate to make colonization screening or decolonization CE. Results Nasal screening ($144.07) is CE if the initial infection rate (1.7%) had an ARR of 0.60%. Decolonization with 2% intranasal mupirocin ointment ($5.09) was CE (ARR, 0.02%). A combined decolonization technique (2% intranasal mupirocin ointment, chlorhexidine wipes, chlorhexidine shower, and prophylactic vancomycin: $37.57) was CE (ARR, 0.16%). Varying infection rate as high as 15% demonstrated that CE did not change by maintaining an ARR of 0.16%. CE of the most expensive decolonization protocol was enhanced as the cost of infection treatment increased, with an ARR of 0.03% at $125,000. Conclusions Prophylactic S aureus decolonization techniques can be CE for preventing infection following cochlear implantation. Decolonization with mupirocin is economically justified if it prevents at least 1 infection out of 5000 implants. S aureus colonization screening needed high reductions in infection rate to be CE.