Many tuberculosis control activities are based on principles learned from studies of tuberculosis transmission. To date, these have largely been limited to outbreak investigations in confined geographical regions. In this report conventional and computerized DNA fingerprint- based approaches were integrated to demonstrate that the most widely prevalent strain of Mycobacterium tuberculosis from New York City was cultured from only 1 of 755 patients in San Francisco, Calif, who was a traveling salesman. Large-scale molecular epidemiologic studies may provide a better understanding of the dynamics of tuberculosis transmission between geographic regions and suggest rational measures to interrupt such transmission.