BACKGROUND: The treatment of rifampicin-resistant TB (RR-TB) in children is evolving rapidly. As newer regimens are introduced into routine care, it is vital to compare their outcome and safety with well-characterised clinical cohorts treated with historical regimens.METHODS: Study sample comprised a prospective observational cohort of children on routine RR-TB treatment, enrolled from 2011 to 2015 in Cape Town, South Africa. Children were followed for safety, treatment response and outcome.RESULTS: Of 136 children included, 27 (19.9%) were living with HIV and 48 (37.8%) had severe TB. The median time-to-culture conversion in children with bacteriological confirmation (n = 44) was 28.5 days (IQR 14.5-45). Overall, 118/129 (91.5%) had favourable TB treatment outcomes. Of 106 (77.9%) children who received an injectable drug, 9 (8.5%) developed hearing loss and 7/136 (5.1%) developed other Grade 3 or higher adverse events likely related to treatment.CONCLUSIONS: In this cohort with a substantial proportion of children with severe manifestations of TB and with HIV, TB treatment outcomes were excellent. Apart from hearing loss, few children developed severe adverse events related to treatment. This study provides robust reference data for future evaluation of shorter, injectable-sparing regimens.