We studied two large Mycobacterium tuberculosis genotype clusters associated with recent outbreaks in homeless persons to determine factors associated with these tuberculosis (TB) strains. Isolates from all culture-positive TB cases diagnosed from 1 January 2001 to 31 December 2004 were genotyped. Patients whose isolates had identical restriction fragment length polymorphism patterns and spoligotypes were considered clustered. Health department records were reviewed and reinterviews attempted for clustered cases. Patients with the Cs30 and BEs75 strains were compared to other genotypically clustered cases and to each other. The two largest genotype clusters among homeless persons were the Cs30 strain (n = 105) and the BEs75 strain (n = 47). Fifty-one (49%) patients with the Cs30 strain and 28 (60%) with the BEs75 strain were homeless. Compared to patients with the BEs75 strain, patients with the Cs30 strain were less likely to be respiratory acid-fast bacillus smear positive (51% versus 72%). Furthermore, patients with the BEs75 strain were more likely to be HIV infected (74% versus 42%), which suggests that most patients with this strain advanced to disease after recent infection. Cases in clusters of strains that have been circulating in the community over a long time period, such as the Cs30 strain, require additional investigation to determine whether clustering is a result of recent transmission or reactivation of remote infection.