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Background. Tuberculosis disease develops in only 5%–10% of humans infected with Mycobacterium tuberculosis . The mechanisms underlying this variability remain poorly understood. We recently demonstrated that colony-forming units of M. tuberculosis in cough-generated aerosols are a better predictor of infection than the standard sputum acid-fast bacilli smear. We hypothesized that cough aerosol cultures may also predict progression to tuberculosis disease in contacts.Methods. We conducted a retrospective cohort study of 85 patients with smear-positive tuberculosis and their 369 household contacts in Kampala, Uganda. Index case patients underwent a standard evaluation, and we cultured M. tuberculosis from cough aerosols. Contacts underwent a standard evaluation at enrollment, and they were later traced to determine their tuberculosis status.Results. During a median follow-up of 3.9 years, 8 (2%) of the contacts developed tuberculosis disease. In unadjusted and adjusted analyses, incident tuberculosis disease in contacts was associated with sputum Mycobacterial Growth Indicator Tube culture (odds ratio, 8.2; 95% confidence interval, 1.1–59.2; P = .04), exposure to a high-aerosol tuberculosis case patient (6.0, 1.4–25.2; P = .01), and marginally, human immunodeficiency virus in the contact (6.11; 0.89–41.7; P = .07). We present data demonstrating that sputum and aerosol specimens measure 2 related but different phenomena.Conclusions. We found an increased risk of tuberculosis progression among contacts of high-aerosol case patients. The hypothesis that a larger infectious inoculum, represented by high aerosol production, determines the risk of disease progression deserves evaluation in future prospective studies.