South Africa has a dual high burden of HIV and drug-resistant TB (DR-TB). We sought to understand the association of HIV and antiretroviral therapy status with TB treatment outcomes. This was a retrospective chart review of 246 patients who began treatment at two DR-TB hospitals in Eastern Cape, South Africa between 2017 and 2020. A categorical outcome with three levels was considered: unfavorable, transferred out, and successful. Descriptive statistics and logistic regression were used to compare the individuals without HIV, with HIV and on antiretroviral therapy (ART), and with HIV but not on ART. Sixty-four percent of patients were co-infected with HIV, with eighty-seven percent of these individuals on ART at treatment initiation. The majority (59%) of patients had a successful treatment outcome. Twenty-one percent of patients transferred out, and an additional twenty-one percent did not have a successful outcome. Individuals without HIV had more than three and a half times the odds of success compared to individuals with HIV on ART and more than ten times the odds of a successful outcome compared to individuals with HIV not on ART (OR 3.64, 95% CI 1.11, 11.95; OR 10.24, 95% CI 2.79, 37.61). HIV co-infection, especially when untreated, significantly decreased the odds of treatment success compared to individuals without HIV co-infection.