Nontuberculous mycobacteria (NTM) are ubiquitous environmental microorganisms. Infection is thought to result primarily from exposure to soil and/or water sources. NTM disease prevalence varies greatly by geographic region, but the geospatial factors influencing this variation remain unclear. To identify sociodemographic and environmental ecological risk factors associated with NTM infection and disease in Colorado. We conducted an ecological study, combining data from patients with a diagnosis of NTM disease from National Jewish Health's electronic medical record database and ZIP code-level sociodemographic and environmental exposure data obtained from the U.S. Geological Survey, the U.S. Department of Agriculture, and the U.S. Census Bureau. We used spatial scan methods to identify high-risk clusters of NTM disease in Colorado. Ecological risk factors for disease were assessed using Bayesian generalized linear models assuming Poisson-distributed discrete responses (case counts by ZIP code) with the log link function. We identified two statistically significant high-risk clusters of disease. The primary cluster included ZIP codes in urban regions of Denver and Aurora, as well as regions south of Denver, on the east side of the Continental Divide. The secondary cluster was located on the west side of the Continental Divide in rural and mountainous regions. After adjustment for sociodemographic, drive time, and soil variables, we identified three watershed areas with relative risks of 12.2, 4.6, and 4.2 for slowly growing NTM infections compared with the mean disease risk for all watersheds in Colorado. This study population carries with it inherent limitations that may introduce bias. The lack of complete capture of NTM cases in Colorado may be related to factors such as disease severity, education and income levels, and insurance status. Our findings provide evidence that water derived from particular watersheds may be an important source of NTM exposure in Colorado. The watershed with the greatest risk of NTM disease contains the Dillon Reservoir. This reservoir is also the main water supply for major cities located in the two watersheds with the second and third highest disease risk in the state, suggesting an important possible source of infection.