Childhood tuberculosis (TB) is a marker of TB transmission within a community. We present the fourth consecutive survey of children with culture-confirmed TB at a hospital in Cape Town, South Africa, from 2009 to 2011. In comparison to the previous survey, the rate of multidrug-resistant TB (MDR-TB) has stabilised and the human immunodeficiency virus infection rate has declined. We also report on the first systematic surveillance of resistance to second-line drugs. Two concerns following from this are the high rate (22%) of ofloxacin resistance in MDR-TB isolates, and the discordance between isolates with an inhA promoter region mutation, usually implying ethionamide (ETH) resistance, and phenotypic ETH results in these isolates showing ETH susceptibility.