Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia cause significant morbidity and mortality in hospitalized patients. Using a nested case-control design, 204 MRSA bacteraemia cases were compared to 301 unmatched methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia controls and were matched 1:2 with non-infected controls. The independent risk factors for MRSA bacteraemia compared to MSSA bacteraemia were older age (P = 0·048), major organ transplant during current hospital stay (P = 0·016) and quinolone use (P = 0·016). Cases were more likely than non-infected controls to have renal failure (P = 0·003), cirrhosis (P = 0·013), and a central venous catheter (P = 0·003) after controlling for other risk factors. This large case-control study made it possible to assess risk factors for MRSA bacteraemia using two sets of controls and showed that risk factors differed greatly depending on the control group chosen. These results confirm the need for careful selection of appropriate control groups and the need to carefully adjust for underlying severity of illness.