Background/Aims Risks and benefits of simeprevir plus sofosbuvir in patients with advanced cirrhosis are unknown. We assessed the safety and sustained virologic responses (SVR) of simeprevir plus sofosbuvir with and without ribavirin in patients with Child-Pugh (CP)-B/C vs. CP-A cirrhosis and compared to matched untreated controls. Methods Multicenter cohort of adults with HCV genotype 1 and cirrhosis treated with simeprevir plus sofosbuvir with/without ribavirin for 12 weeks. Controls were matched on treatment center, age, CP class and model for end-stage liver disease (MELD) score. Results Of 160 patients treated with simeprevir plus sofosbuvir with/without ribavirin, 35% had CP-B/C and 64% had CP-A, with median baseline MELD 9 (IQR 8–11). SVR12 was achieved by 73% of CP-B/C vs. 91% of CP-A (p<0.01). CP-B/C vs. CP-A had more early treatment discontinuations (11% vs. 1%), adverse events requiring hospitalization (22% vs. 2%), infections requiring antibiotics (20% vs. 1%) and hepatic decompensating events (20% vs. 3%) (all p<0.01). There were 2 deaths: 1 CP-B/C (liver-related) and 1 CP-A (not liver-related). In multivariate analysis, CP-B/C independently predicted lack of SVR12 (OR 0.27, 95% CI 0.08–0.92). In comparing simeprevir plus sofosbuvir treated patients vs. matched untreated controls, adverse events requiring hospitalization (9% vs. 13%, p=0.55), infections (8% vs. 6%, p=0.47) and events of decompensation (9% vs. 10%, p=0.78) occurred at similar frequency. Conclusions Simeprevir plus sofosbuvir with/without ribavirin has lower efficacy and higher rates of adverse events in patients with CP-B/C cirrhosis compared to CP-A. The frequency of adverse safety outcomes were similar to matched untreated controls, suggesting safety events reflect the natural history of cirrhosis and are not related to treatment.