Reduced vancomycin susceptibility (RVS) may lead to poor clinical outcomes in Staphylococcus aureus bacteraemia. We conducted a cohort study of 392 patients with S. aureus bacteraemia within a university health system. The association between RVS, as defined by both Etest [vancomycin minimum inhibitory concentration (MIC) >1·0 μg/ml] and broth microdilution (vancomycin MIC ≥1·0 μg/ml), and patient and clinical variables were evaluated to create separate predictive models for RVS. In total, 134 (34·2%) and 73 (18·6%) patients had S. aureus isolates with RVS by Etest and broth microdilution, respectively. The final model for RVS by Etest included methicillin resistance [odds ratio (OR) 1·51, 95% confidence interval (CI) 0·97-2·34], non-white race (OR 0·67, 95% CI 0·42-1·07), healthcare-associated infection (OR 0·56, 95% CI 0·32-0·96), and receipt of any antimicrobial therapy ≤30 days prior to the culture date (OR 3·06, 95% CI 1·72-5·44). The final model for RVS by broth microdilution included methicillin resistance (OR 2·45, 95% CI 1·42-4·24), admission through the emergency department (OR 0·54, 95% CI 0·32-0·92), presence of an intravascular device (OR 2·24, 95% CI 1·30-3·86), and malignancy (OR 0·51, 95% CI 0·26-1·00). The availability of an easy and rapid clinical prediction rule for early identification of RVS can be used to help guide the timely and individualized management of these serious infections.