The aims of this case-control study were to describe the characteristics of cystic fibrosis (CF) patients who isolated Stenotrophomonas maltophilia in sputum, to determine risk factors for acquisition, to assess persistence of the organism and clinical outcomes postacquisition. Data were collected from 1991-1999. CF patients and controls (who had never isolated S. maltophilia) were matched for age (+/- 1 yr), sex and forced expiratory volume in one second (+/- 10%). Data were collected from the year prior and for 2 yrs postacquisition of S. maltophilia. The prevalence of S. maltophilia increased from 3.3% to 15%. Factors associated with S. maltophilia acquisition were more than two courses of intravenous antibiotics, isolation of Aspergillus fumigatus in sputum and oral steroid use. The effect of A. fumigatus was independent of steroid use. Clinical status did not change postacquisition. The majority of patients cleared the organism from the sputum. Long-term infection or an accelerated deterioration in lung function or nutrition is not likely post-Stenotrophomonas maltophilia acquisition in cystic fibrosis. This is the first documentation of an association between Aspergillus fumigatus isolation and Stenotrophomonas maltophilia acquisition in cystic fibrosis, independently of steroid therapy.