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Background Guidelines recommend withholding sofosbuvir ( SOF) in patients with an estimated glomerular filtration rate ( eGFR) of less than 30 mL/min. Aim To assess the risk of acute kidney injury ( AKI) in patients with no renal contraindications for SOF-based treatment. Methods This multicenter retrospective observational study included all consecutive patients that were treated with SOF-based or telaprevir/boceprevir (TVR/BOC)-based regimens at two tertiary university centers in North America. AKI was defined as an increase of ≥0.3 mg/ dL (≥26.5 μmol/L) in serum creatinine level. Multivariable logistic regression analysis was used to identify risk factors for the occurrence of AKI. Results In total, 426 patients were included and treated with a SOF-based regimen (n=233, 54.7%) or TVR/ BOC-based regimen (n=193, 45.3%). Among patients treated with a TVR/ BOC-based regimen 34 (18%) of 193 patients experienced AKI compared to 26 (11%) of 233 patients treated with SOF-based regimens ( P=.056). Multivariable logistic regression analysis showed that the presence of ascites ( OR: 4.44, 95% CI: 1.46-13.54, P=.009) and the use of NSAIDs ( OR: 4.47, 95% CI: 1.32-15.19, P=.016) were associated with a risk of AKI during SOF-based antiviral therapy. Creatinine levels returned to normal at end of follow-up in 23 (88%) of the 26 patients who experienced AKI with a SOF-based regimen and had a creatinine level available during follow-up. Conclusions Although the risk for AKI was lower than for patients treated with TVR/ BOC-based regimens, AKI was seen during 11% of SOF-based regimens and was mostly reversible. Patients with ascites and patients using NSAIDs have an increased risk for AKI during SOF-based antiviral therapy. [ABSTRACT FROM AUTHOR]