Objective This study compared the costs and patient movements of a new hospital protocol to discontinue contact precautions for patients with non-multiresistant methicillin-resistant Staphylococcus aureus (nmMRSA), based on whole-genome sequencing (WGS) of pathogens with current practice. Methods A hybrid simulation model was constructed and analysed over a 12-month time horizon. Six multidrug-resistant organisms and influenza were modelled concurrently where infected patients competed for isolation beds. Model inputs included pathogen incidence, resources for WGS, staff and contact precautions, hospital processes, room allocations and their associated costs. Data were sourced from aggregated records of patient admissions during 2017-18, clinical records and published reports. Results The WGS protocol resulted in 389 patients isolated (44% of current practice), 5223 'isolation bed days' (56%) and 268 closed-bed days (88%). Over 1 year, the mean (±s.d.) total cost for the WGS protocol was A$749243±126667; compared with current practice, the overall cost savings were A$690864±300464. Conclusion Using WGS to inform infection control teams of pathogen transmission averts patients from isolation rooms and reduces significant resources involved in implementing contact precautions. What is known about the topic? There are an estimated 265000 hospital-acquired infections (HAI) in Australia each year. WGS can accurately identify the genetic lineage among HAIs and determine transmission clusters that can help infection control staff manage patients. Economic appraisals are lacking to inform whether pathogen genomics services should be adopted within already-stretched hospital budgets. What does this paper add? An isolation protocol using pathogen genomics to provide additional information on the relatedness of a pathogen between colonised patients showed favourable results for healthcare costs and patient flow. Using WGS, in a confirmatory role, to discontinue certain patients from contact precautions and isolation rooms resulted in cost savings of A$690864 across 1 year for a single major hospital. What are the implications for practitioners? Using pathogen WGS services for infection control potentially curbs hospital spending, averts patient isolations and improves patient flow within hospitals.