Pulmonary manifestations of interferon (IFN) use are a rare but well known complication seen with both standard and pegylated interferon alpha-2b (pegIFNalpha-2b) forms of the agent. These are generally of modest intensity and reversible. We report the first case of fulminant adult respiratory distress syndrome (ARDS) associated with pegylated interferon alpha-2a (pegIFNalpha-2a) and ribavirin use for hepatitis C, complicated by subsequent and ultimately fatal sepsis and multiorgan failure. Practicing gastroenterologists and intensivists alike need to be aware of the potential for serious pulmonary sequelae with the use of combination therapy for chronic hepatitis C viral (CHCV) infections.