Recently developed molecular techniques have revolutionized the epidemiology of tuberculosis. Multiple studies have used these tools to examine the population structure of Mycobacterium tuberculosis isolates in different communities. The distributions of clusters of M. tuberculosis isolates in these settings may variously reflect social mixing patterns or the differential fitness of specific clones of the organism. We developed an individual-based microsimulation of tuberculosis transmission to explore social and demographic determinants of cluster distribution and to observe the effect of transmission dynamics on the empiric data from molecular epidemiologic studies. Our results demonstrate that multiple hostrelated factors contribute to wide variation in cluster distributions even when all strains of the organism are assumed to be equally transmissible. These host characteristics include interventions such as chemotherapy, vaccination and chemoprophylaxis, HIV prevalence, the age structure of the population, and the prevalence of latent tuberculosis infection. We consider the implications of these results for the interpretation of cluster studies of M. tuberculosis as well as the more general application of microsimulation models to infectious disease epidemiology.O ver the past 10 years, molecular tools have become available that have changed the way that epidemiologists study the transmission of infectious disease (1). In addition to their role in detecting unsuspected transmission links (2-4), molecular markers are increasingly being used to study transmission patterns within populations and to evaluate host-and strain-specific risk factors for disease spread (5, 6). Nowhere has this approach been used more rigorously than in the pioneering work on the molecular epidemiology of tuberculosis (TB). Since the development of standardized methods for DNA fingerprinting of Mycobacterium tuberculosis, molecular techniques have been used to estimate the fraction of cases attributable to recent transmission of M. tuberculosis (7-14), identify host-specific risk factors for disease spread (15-18), document exogenous reinfection (19-21), and study patterns of drug resistance (22)(23)(24). Investigators also have begun to use these methods to explore potential strain-specific differences in bacterial phenotypes such as tissue tropism, virulence, and transmissibility (25,26).This research has shown that the genetic diversity of M. tuberculosis isolates from different human communities can vary considerably (27,28). Clusters of identical isolates are assumed to share DNA fingerprints as a result of the spread of the organism among the human hosts who harbor the isolates in the cluster. Patients with TB whose isolates cannot be grouped into clusters, i.e., those with unique DNA fingerprints, are assumed to have disease that results from the reactivation of latent infection acquired in the past. Variation in the distribution of clusters of M. tuberculosis isolates in different communities is thought to reflect different TB...