Rationale: The multidrug-resistant (MDR) and extensively drug-resistant tuberculosis (XDR TB) epidemics are rapidly expanding in South Africa. Our initial report of HIV-associated XDR TB in South Africa revealed rapid and near complete mortality. Lower mortality has been described in the literature, but few of these patients have been HIV co-infected. Objectives: To characterize mortality from MDR and XDR TB in a setting with high HIV co-infection rates. Methods: Retrospective observational study among 654 MDR and XDR TB cases diagnosed in Tugela Ferry, South Africa, from 2005–2007. Demographics and HIV status were abstracted from available medical records. Measurements: Survival was determined from the date of sputum collection until October 2008 and correlated with year of diagnosis and drug-susceptibility test results. Main Results: From 2005–2007, 272 MDR TB and 382 XDR TB cases were diagnosed; HIV co-infection rates were 90% and 98%, respectively. One-year mortality was 71% for MDR and 83% for XDR TB patients; 40% of MDR TB and 51% of XDR TB cases died within 30 days of sputum collection. One-year mortality among both MDR and XDR TB patients improved from 2005 to 2007; however, the majority of deaths still occurred within the first 30 days. One-year and 30-day mortality rates were worse with greater degree of drug-resistance (p<.001). Conclusions: Mortality from MDR and XDR TB in this high HIV-prevalence region is extraordinarily high, particularly within the first 30 days. Efforts to reduce mortality must focus on earlier diagnosis and early initiation of second-line TB and antiretroviral therapy.