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Summary Background The South African Electronic Drug-Resistant Tuberculosis Register (EDRweb) is the national database of registered drug-resistant tuberculosis (DR-TB) cases. Methods This study was a retrospective, de-identified secondary analysis of EDRweb patients initiating treatment for rifampicin-resistant TB (January 2009 to September 2011). The relative risks of death and treatment success were estimated using modified Poisson regression with robust error estimation. Results Seventeen thousand six hundred and ninety-seven cases of DR-TB were registered and met the inclusion criteria; 52.0% ( n = 9207) were male and the median age was 35 years (interquartile range 27–43 years). Of the 9419 cases with HIV infection (53.2%), 7157 (76.0%) were on antiretroviral therapy. Most had undergone previous TB treatment (76.5%, n = 13 531). Multidrug-resistant TB was the most common diagnosis, at 80.6% ( n = 14 272). No treatment outcome was available for 6934 patients (39.2%). For patients with outcomes, 4227 (39.4%) were successfully treated, 2987 (27.8%) died, 2533 (23.7%) were lost to follow-up, and 996 (9.3%) failed. Second-line drug resistance was the strongest predictor of death during DR-TB treatment; extensively drug-resistant TB patients were more likely to have died during treatment (adjusted relative risk 2.63, 95% confidence interval 2.45–2.84). Conclusions Testing for second-line drug resistance at initiation of DR-TB treatment can identify patients most at risk of treatment failure and death and most in need of individualized treatment. [ABSTRACT FROM AUTHOR]