ABSTRACT: RATIONALE:Pulmonary nontuberculous mycobacteria (NTM) disease represents a significant threat to patients with cystic fibrosis (CF), with an estimated annual prevalence of 12%. Prior studies reported an increasing annual NTM prevalence in the general population, though similar trends in persons with CF have not been assessed. OBJECTIVES:In this study we aimed to identify the prevalence, geographic patterns, temporal trends, and risk factors for NTM positivity by mycobacterial species among persons with CF throughout the United States. METHODS:Using annualized CF Patient Registry (CFFPR) data from 2010 to 2014, we identified patients with mycobacterial culture results to estimate the annual and period prevalence of pathogenic NTM species by demographic and geographic factors. Regression models were used to estimate the annual percent change over time and risk factors for NTM isolation. Geographic patterns were described and mapped. RESULTS:Of 16,153 included persons with CF, 3,211 (20%) had a pathogenic NTM species isolated at least once over the 5-year period; 1,949 (61%) had Mycobacterium avium complex (MAC), and 1,249 (39%) had M. abscessus. The period prevalence was 12% for MAC (confidence interval [CI], 12-13%), 8% for M. abscessus (CI, 7-8%), and 4% for other NTM species (CI, 3.8-4.3%). The period prevalence for MAC was nearly three times greater among patients ≥60 years old with a body mass index < 19 (33% [CI, 16-51%]); this trend was not present for patients with M. abscessus (4% [CI, 0-11%]). NTM prevalence showed a significant relative increase of 5% per year, from 11.0% in 2010 to 13.4% in 2014 (P = 0.0008), although this varied by geographic area. For M. abscessus, the states with the highest prevalence were Hawaii (50%), Florida (17%), and Louisiana (16%), and for MAC they were Nevada (24%), Kansas (21%), and Hawaii and Arizona (both 20%). Study participants with either MAC or M. abscessus were significantly more likely to have been diagnosed with CF at an older age (P < 0.0001), have a lower body mass index (P < 0.0001), higher forced expiratory volume in 1 second % predicted (P < 0.01), and fewer years on chronic macrolide therapy (P < 0.0001). CONCLUSIONS:NTM remains highly prevalent among adults and children with CF in the United States, with one in five affected, and appears to be increasing over time. Prevalence varies by geographic region and by patient-level factors, including older age and receiving an initial CF diagnosis later in life. Routine screening for NTM, including mycobacterial speciation, especially in high-risk geographic areas, is critical to increase our understanding of its epidemiology and changes in prevalence over time.