Abstract Background There are limited data on the real-world effectiveness of direct-acting antiviral (DAA) treatment in patients coinfected with hepatitis C virus (HCV) and HIV—a population with complex challenges including ongoing substance use, cirrhosis, and other comorbidities. We assessed how patient characteristics and the appropriateness of HCV regimen selection according to guidelines affect treatment outcomes in coinfected patients. Methods We included all patients who initiated DAA treatment between November 2013 and July 2017 in the Canadian Co-Infection Cohort. Sustained virologic response (SVR) was defined as an undetectable HCV RNA measured between 10 and 18 weeks post-treatment. We defined treatment failure as virologic failure, relapse, or death without achieving SVR. Bayesian logistic regression was used to estimate the posterior odds ratios (ORs) associated with patient demographic, clinical, and treatment-related risk factors for treatment failure. Results Two hundred ninety-five patients initiated DAAs; 31% were treatment-experienced, 29% cirrhotic, and 80% HCV genotype 1. Overall, 92% achieved SVR (263 of 286, 9 unknown), with the highest rates in females (97%) and lowest in cirrhotics (88%) and high-frequency injection drug users (89%). Many patients (38%) were prescribed regimens that were outside current clinical guidelines. This did not appreciably increase the risk of treatment failure—particularly in patients with genotype 1 (prior odds ratio [OR], 1.5; 95% credible interval [CrI], 0.38–6.0; posterior OR, 1.0; 95% CrI, 0.40–2.5). Conclusions DAAs were more effective than anticipated in a diverse, real-world coinfected cohort, despite the use of off-label, less efficacious regimens. High-frequency injection drug use and cirrhosis were associated with an increased risk of failure.