The South Carolina Tuberculosis (TB) Control Division ranked all the TB genotype clusters (two or more cases with matching genotypes) in the state based on the number of cases. The largest cluster, PCR00002, was investigated to determine if the cluster represented recent Mycobacterium tuberculosis transmission, and if so, to identify associated risk factors. The PCR0002 cluster, which included pediatric cases, clearly represented recent M. tuberculosis transmission. The two primary factors contributing to cluster growth were substance abuse and recurrent TB disease. Elimination of ongoing M. tuberculosis transmission in this population will require concurrent treatment for TB disease and substance abuse.