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Background: According to the World Health Organization, South Africa ranks as one of the highest burden of TB, TB/HIV co-infection, and drug-resistant TB (DR-TB) countries. DR-TB treatment is complicated to administer and relies on the use of multiple toxic drugs, with potential for severe adverse drug reactions. We report the occurrence of adverse events (AEs) during a standardised DR-TB treatment regimen at two outpatient, decentralized, public-sector sites in Johannesburg, South Africa. Methods: We reviewed medical records of the six-month intensive treatment phase for rifampicin-resistant (RR) TB patients registered May 2012 - December 2014. Patients contributed follow-up time until death, loss from treatment, censoring (6 months) or data extraction. A standardized regimen of kanamycin, moxifloxacin, ethionamide, terizidone, and pyrazinamide was used according to national guidelines. AEs were graded using the AIDS Clinical Trial Group scale. We present subhazard ratios from competing risk analysis for time to severe AE, accounting for mortality and loss from treatment. Results: Across the two sites, 578 eligible patient files were reviewed. 36.7% were categorized as low weight (=50 kg) at DR-TB initiation. 76.0% had no history of TB treatment prior to the current episode of RR TB. 26.8% were diagnosed with RR TB while hospitalized, indicating poor clinical condition. 82.5% of patients were also HIV positive, of whom 43. 8% were on ART prior to RR TB treatment and 32.1% initiated ART with or after RR TB treatment. Median CD4 count was 114.5 (IQR: 45-246.5). Overall, 578 reports of AEs were captured for 204 patients (35.3%) and 110 patients (19.0%) had at least one severe AE reported. Patients with at least one AE experienced a median of 3 (IQR: 2-4) AEs per patient. HIV-positive patients with CD4 counts =100 cells/mm³ and those newly initiating ART were more likely to experience a severe AE (sHR: 2.76, 95% CI: 1.30-5.84 and sHR: 3.07, 95% CI: 1.46-6.46, respectively). Conclusion: Severe AE are common during the first 6 months of RR TB treatment and HIV-positive patients newly initiating ART have the highest subdistribution hazard ratio for severe AE, accounting for the competing risks of death and loss from treatment. [ABSTRACT FROM AUTHOR]