Vulnerable populations are disproportionately affected by hepatitis C virus (HCV) infection and experience high rates of health disparity. There are no data on real-world experience with highly efficacious direct-acting anti-HCV treatment in this population. We aimed to evaluate the real-world experience with sofosbuvir-based regimens among a vulnerable HCV-infected population. HCV treatment response was assessed among 204 patients who completed 12-24 weeks of sofosbuvir-based regimens (in combination with pegylated interferon and ribavirin, simeprevir, ledipasvir, or daclatasvir) at the San Francisco safety-net healthcare system liver specialty clinic between January 2014 and December 2015. Virologic response during therapy was assessed at weeks 4 and 8, end of therapy, and 12-week treatment discontinuation (SVR 12). Patient characteristics were median age 58 years, 60 % male, 42 % Caucasian (21 % black, 19 % Hispanic), 72 % had genotype 1 (23 % genotype 2 or 3), and the median baseline log(10) HCV viral load was 6.1 IU/ml and alanine transaminase 63 U/l. Cirrhosis was present in 36 % (of whom 40 % were decompensated), and 18 % were HCV treatment-experienced. Overall, SVR 12 was achieved in 97 % (99 % genotype 1, 100 % genotype 2, 84 % genotype 3). Five of six (83 %) patients who relapsed had decompensated cirrhosis, and 67 % were also non-adherent to therapy. On-treatment virologic response did not impact SVR. High rates of sustained virologic response can be achieved in safety-net HCV-infected patients. Access to DAA-based regimens is critical to addressing HCV-related health disparity in this at-risk population.