Background: Cirrhosis is the final common pathway of hepatic inflammation and fibrosis caused most commonly by alcohol or viral infection with hepatitis C and/or B. HMG-coA reductase inhibitors (statins) are thought to be beneficial in liver disease by ameliorating intrahepatic endothelial dysfunction, inflammation and fibrosis, thereby leading to a reduction in portal pressure. Because clinically significant portal hypertension is the main driver of decompensation, a reduction in portal pressure (demonstrated in both experimental and human cirrhosis) will prevent hepatic decompensation. Objectives: This phase III, randomized, double-blind, placebo-controlled, multi-center study will assess whether simvastatin can delay/prevent hepatic decompensation, hepatocellular carcinoma (HCC), need for liver transplantation or death in Veterans with compensated cirrhosis at a high-risk of decompensation. Specific Aims: 1) To demonstrate that statin therapy in patients with cirrhosis at high-risk for hepatic decompensation will reduce the incidence of hepatic decompensation, hepatocellular carcinoma, all-cause mortality and need for liver transplantation; 2) to assess the impact of statin exposure on health-related quality of life in patients with compensated cirrhosis; and 3) to explore the impact of chronic simvastatin on portal hypertension in patients with compensated cirrhosis. Study Design: Patients with compensated cirrhosis at high-risk for hepatic decompensation will be stratified based upon the presence or absence of varices and randomized to simvastatin 40mg/day or placebo for up to 24 months. Patients will be observed for the development of hepatic decompensation (variceal hemorrhage, ascites, encephalopathy), HCC, liver-related death, death from any cause, and/or complications of statin therapy. The primary study endpoint is the effect of statin therapy on reducing the incidence of hepatic decompensation and HCC. Secondary endpoints are to assess the effect of statin therapy on mortality, need for liver transplantation, health related quality of life in patients with decompensated cirrhosis, to assess the impact of statins on portal hypertension, and to explore the interaction of SLCO1B1 and KIF6 polymorphisms on safety and clinical efficacy of statin therapy. Clinical Impact: There are an estimated 35,000 individuals with cirrhosis receiving ongoing medical care within the VA healthcare system. Approximately 15,000 liver decompensation-related hospitalizations occur annually in the VA with a mean length of stay of 9 days. The current estimated total healthcare expenditure for an ‘average’ Veteran with cirrhosis approximates $23,000 per year, three times greater than age- matched controls. Patients with decompensated cirrhosis have nearly double the annual costs, predominantly related to hospitalizations. Simvastatin, at a cost of $25-50 per year, if proven to safely reduce liver decompensation and death, would have tremendous health benefits fo...