Background. There is increasing evidence of a strain-related variation in the virulence in Mycobacterium tuberculosis that may afford a selective advantage to certain strains. The W-Beijing strain family is globally distributed, highly virulent in animal models, associated with human immunodeficiency virus infection and drug resistance, and may be an emerging strain family. Our goal was to determine whether W-Beijing strains are expanding in a region of South Africa where rates of tuberculosis are among the highest in the world. Methods. We used spoligotyping and single nucleotide polymorphism analysis to genotype all strains of tuberculosis from children presenting to the major pediatric referral hospital in Cape Town, South Africa over a period of 4 years and strains present in 352 archived histological samples from over a 76-year period. Results. The proportion of W-Beijing strains from children increased from 13% to 33% from 2000 to 2003 (P = .026). With regard to the histological samples, W-Beijing strains were absent in the samples from the period 1930-1965 and rare in the samples from the period 1966-1995 (2.8% of samples), but they were increasingly common in samples from the period 1996-2005 (20% of samples; P = .001). Conclusions. The rapid expansion of W-Beijing strains in a region with a very high background incidence of tuberculosis suggests that these strains have a significant selective advantage. The biological reasons for this observation remain unclear but warrant further study. The rapid spread of this virulent strain lineage is likely to present additional challenges for tuberculosis control.