Because tuberculosis (TB) is a public health threat that continues to elude elimination in the United States, there is a need to identify contributing factors that may have implications for targeted control measures. Molecular studies of genetic clustering are crucial for pinpointing these contributing factors. It is for this reason this study was conducted. This was a non-experimental, cross-sectional population-based molecular epidemiological study of TB in SC from 2005 to 2011. Its purpose was to estimate the proportion of TB that may be due to recently acquired infection and to determine the risk factors associated with the genetic clustering of identical M. tuberculosis isolates from TB patients in South Carolina from 2005-2011. The analysis sample included 627 confirmed pulmonary and/or pleural cases of TB, for which complete data on all covariates and a valid genotype were available. The results strongly suggested that about 50% of TB in South Carolina is recently transmitted. The study also revealed that being born in the United States and Black race were independently and significantly associated with being part of a TB genotype cluster. The key messages of this study were as follows: a substantial portion of TB in South Carolina is due to recent transmission, not reactivation or importation, and transmission of TB in South Carolina occurs in groups often defined by American birth and Black race. These important findings indicate that most TB in South Carolina is preventable and that enhanced TB control efforts should be explored. The implication for positive social change is that employing targeted contact investigation informed by these findings could lead to decreased disease transmission. Future studies should explore pilot programs that investigate alternatives to the traditional TB contact investigation.