Stenotrophomonas maltophilia (SM) was recovered from 211 of 773 cystic fibrosis (CF) patients followed for at least one year, and seen between 1982 and 1994. Yearly prevalence (5.6% to 8.7%) and incidence rates (1.6% to 5.7%) showed no trends. SM persistence varied greatly and was unlike that of Pseudomonas aeruginosa. Fifty percent of SM-positive patients had only one positive culture and only 24 (11%) remained chronically infected. Although SM-positive patients were more likely to be hospitalized than SM-negative patients, for 55% of SM-positive patients, acquisition did not appear to follow hospitalization. Of 40 SM-positive patients who had a CF sibling, only 10 siblings were ever culture positive. When stratified by FEV1, the two-year survival for SM-positive with mild/moderate disease (98%) and severe disease (78%) was similar to that of our SM-negative patients. Five-year survival was only 40% for SM-positive patients with initially severe pulmonary status, compared with 72% for the SM-negative patients. Seventy percent of the original SM isolates were panresistant (susceptible to no more than one antimicrobial agent). Ten years later, panresistance was 84%. Despite our reassuring experience with SM, including lack of sibling concordance, the fact that the majority of our patients had no hospital exposure prior to acquisition, the high incidence of transient infection, and the seemingly unaffected two-year survival, there are insufficient data to definitively conclude that segregation of these patients would be beneficial. The increasing prevalence of multiply resistant gram-negative pathogens in CF patients suggests the need for continued caution with any panresistant pathogen.