With the increasing lifespan of persons with cystic fibrosis (CF), the emergence of a variety of previously seldom seen pathogens, including the nontuberculous mycobacteria (NTM), has been seen. Determining the impact of these indolent organisms on the natural history of cystic fibrosis lung disease has been difficult. We initiated a two-stage study in 1993 to assess the prevalence and clinical impact of these organisms among persons with CF in US CF Centers. These organisms were frequently recovered from older patients with relatively mild disease. While over the short, 15-month course of follow-up no significant differences in the rate of decline of lung function attributable to NTM were seen, concerning changes and progression of high-resolution computed tomography findings were seen in patients from whom these organisms were repeatedly recovered.