Sofosbuvir, a nucleotide inhibitor of the hepatitis C virus (HCV) polymerase, is a component of several all-oral HCV therapies. GS-331007, sofosbuvir’s predominant metabolite, is renally eliminated and accumulates 5-fold to 20-fold in patients with advanced chronic kidney disease (CKD) or undergoing hemodialysis, respectively. Pre-clinical data did not determine whether these exposures represented a risk for toxicity. Therefore, subjects with advanced CKD were not included in registrational studies, and sofosbuvir was not initially approved for use in advanced CKD. Nevertheless, after initial licensing, off-label use of sofosbuvir at full or reduced doses was reported in patients with kidney disease. Two clinical trials of sofosbuvir-containing therapies were conducted in patients with end-stage kidney disease demonstrating safety and efficacy. These led to expanded FDA approval in 2019 for the use of sofosbuvir-containing regimens in patients with advanced CKD, including dialysis dependence. Even so, given the availability of protease-inhibitor containing DAA regimens, there was a reluctance by some practitioners to use sofosbuvir-containing regimens in moderate to severe renal disease. Here we review the existing data on sofosbuvir’s pharmacokinetics, toxicology, efficacy, and safety in patients with kidney disease. Data from both clinical trials and real-world practice settings indicate that in patients with moderate to severe kidney disease, full-dose sofosbuvir-based regimens have high rates of efficacy and acceptable safety and tolerability profiles, without increased risk for cardiac adverse events or clinically meaningful changes in kidney function. Conclusion. Sofosbuvir-based regimens are safe and effective in patients who have moderate to severe kidney disease, including those undergoing hemodialysis.© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.