Methicillin-resistant Staphylococcus aureus (MRSA) is an increasing problem for patients with cystic fibrosis (CF). It has been associated with clinical deterioration in some patients with CF, creates additional infection control problems, and may affect acceptance onto transplant waiting lists. Recent attempts to eradicate the organism have met with only moderate success. An understanding of those factors which increase the risk of acquisition of MRSA by CF patients will aid the development of effective preventative strategies. We conducted a retrospective case-control study comparing a variety of risk factors for 15 MRSA-positive patients and 30 age-sex-matched MRSA-negative controls who attended the Regional Paediatric or Regional Adult Cystic Fibrosis Units in Leeds. During the year prior to initial isolation, MRSA-positive CF patients spent more days in hospital (mean 19.8 days versus 5.5 days, p=0.0003), received more treatment days of oral ciprofloxacin (43.5 days versus 13.9 days, p=0.03) more treatment days of oral/intravenous cephalosporins (42.7 days versus 15.4 days, p=0.04) and were more likely to be chronically infected with Aspergillus fumigatus (40% versus 10%, p=0.04) than the age-sex-matched MRSA-negative controls. There were no significant differences in observed clinical parameters (clinical and X-ray scores) with between the two groups. Minimising the number and length of hospital admissions and judicious use of antibiotics, particularly ciprofloxacin, should be the key components of any strategies designed to reduce the risk of MRSA acquisition by patients with CF.