During October 2005, four children in a school in Cape Town were identified with multidrug-resistant tuberculosis (MDR-TB). Genetic analysis confirmed that these isolates belonged to a single cluster (Beijing cluster 220) and that all harboured a -15 inhA(C-T) promoter mutation demonstrating transmission. Genetic analysis of isolates cultured from patients from the Boland-Overberg-South Cape-Karoo and Cape Town regions showed that 28% (58/209) of patients infected with a Beijing strain had the cluster 220 genotypes and that all harboured the same -15 inhA(C-T) promoter mutation. The presence of these transmissible MDR-TB strains may pose a threat to the community, and rigorous infection control measures are needed to ensure the safety of those exposed.