OBJECTIVE Antibiotic resistance is a major threat to public health. Resistance is largely driven by antibiotic usage, which in many cases is unnecessary and can be improved. The impact of decreasing overall antibiotic usage on resistance is unknown and difficult to assess using standard study designs. The objective of this study was to explore the potential impact of reducing antibiotic usage on the transmission of multidrug-resistant organisms (MDROs). DESIGN We used agent-based modeling to simulate interactions between patients and healthcare workers (HCWs) using model inputs informed by the literature. We modeled the effect of antibiotic usage as (1) a microbiome effect, for which antibiotic usage decreases competing bacteria and increases the MDRO transmission probability between patients and HCWs and (2) a mutation effect that designates a proportion of patients who receive antibiotics to subsequently develop a MDRO via genetic mutation. SETTING Intensive care unit INTERVENTIONS Absolute reduction in overall antibiotic usage by experimental values of 10% and 25% RESULTS Reducing antibiotic usage absolutely by 10% (from 75% to 65%) and 25% (from 75% to 50%) reduced acquisition rates of high-prevalence MDROs by 11.2% (P<.001) and 28.3% (P<.001), respectively. We observed similar effect sizes for low-prevalence MDROs. CONCLUSIONS In a critical care setting, where up to 50% of antibiotic courses may be inappropriate, even a moderate reduction in antibiotic usage can reduce MDRO transmission. Infect Control Hosp Epidemiol 2017;38:663-669.