Introduction: Patients with HCV and cirrhosis have the greatest need for treatment. Many of these patients have failed previous treatment and are at high risk of decompensation if treated with a regimen containing PEGINF/RBV. SOF, a polymerase inhibitor, and SMV, a protease inhibitor, are highly effective in suppressing HCV genotype 1. SOF+SIM have been utilized together in patients with prior null response and cirrhosis. However, the safety and efficacy of SOF+SMV in patients with cirrhosis and contraindications to PEGINF/RBV has not yet been evaluated. Methods: Seventy-five consecutive patients with chronic HCV, cirrhosis, and contraindications to PEGINF/RBV initiated 12 weeks of treatment with SOF+SMV, since these agents were FDA-approved in December 2013. To date, all patients have received at least 2 weeks of treatment. Contraindications to PEGINF/RBV included platelet count <70 (30), hemoglobin <10 (3), previous complications of cirrhosis; ascites (10), variceal bleeding (8), hepatic encephalopathy (20), or HCC (1); age >65 years (15), symptomatic cryoglobulinemia (5), serum creatinine >1.5 mg/dL (5), and prior intolerance to PEGINF (4). Several patients had multiple contraindications. Results: The mean age was 60 years (29-79), 65% were male, 42% black, 67% genotype 1A, mean log HCV RNA 6.1 IU/mL, 94% IL28B non-CC, 43% treatment-naïve, 23% failed prior treatment with PEGINF, and 19% failed prior treatment with boceprevir or telaprevir. Mean MELD score at initiation of treatment was 13.2; 6 patients had a MELD >15. To date, the number of patients completing 4, 8, and 12 weeks of treatment are 64, 50, and 31, respectively. At weeks 2, 4, 8, and 12, HCV RNA was undetectable in 37%, 86%, 97%, and 100% of patients. Four out of 5 (80%) achieved SVR4. One patient relapsed. Two patients developed hepatic decompensation after becoming HCV RNA undetectable. Treatment was stopped in both; at week 10 in a patient who then achieved SVR4 and liver function stabilized, and at week 8 in a patient who died. Both patients had prior complications of cirrhosis and MELD of 18 when they initiated treatment. One patient with undetectable HCV RNA developed HCC at treatment week 8 and remains on treatment. Conclusion: This is the first study to evaluate SOF+SIM in patients with cirrhosis and contraindications to PEGINF/RBV. Treatment with SOF+SMV achieves rapid virologic clearance in these patients. Nearly 90% become HCV RNA undetectable within 4 weeks, and all patients appear to eventually become HCV RNA undetectable during the 12-week treatment regimen. Patients with advanced cirrhosis are at risk to develop complications during treatment, but it is unclear if this is increased by treatment. SVR4 will be available on all patients and SVR12 in 50 patients by the ACG meeting in October 2014. Disclosure - Dr Shiffman has participated in advisor meetings with Achillion, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead, Gen-Probe, Globeimmune, GlaxoSmithKline, Janssen, Merck, Novartis, Roche/Genentech and Vertex; is a speaker for Bayer, Gilead, Janssen, Merck, Roche/Genentech and Vertex; and receives grant support from Abbott, Achillion, Beckman-Colter, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead, Globeimmune, Idenix, Intercept, Merck, Mochida, Novartis and Roche/Genentech. Ms Long has participated in advisor meetings with Abbvie, Gilead, Janssen, Kadman, Merck and Vertex; and is a speaker for Merck, GlaxoSmithKline, Kadman, Salix and Vertex. Ms James has participated in advisor meetings with Gilead and Janssen and is a speaker for Janssen. Mr Alexander has participated in advisor meetings with Gilead.