Serious infection is a recognized complication of intravenous drug abuse and a major cause of morbidity and mortality among intravenous drug users. Trends in rates of serious infection and the associated costs related to opioid abuse/dependence have not been previously investigated in the context of the US opioid use epidemic. Our study, using a nationally representative sample of US inpatient hospitalizations, showed that hospitalizations related to opioid abuse/dependence both with and without associated serious infection significantly increased from 2002 to 2012, respectively, from 301,707 to 520,275 and from 3,421 to 6,535. Additionally, inpatient charges for both types of hospitalizations almost quadrupled over the same time period, reaching almost $15 billion for hospitalizations related to opioid abuse/dependence and more than $700 million for those related to associated infection in 2012. Medicaid was the most common primary payer for both types of hospitalizations. Our results characterize the financial burden on the health care system related to opioid abuse/dependence and one of the more serious downstream complications of this epidemic: serious infection. These findings have important implications for the hospitals and government agencies that disproportionately shoulder these costs and for clinicians, researchers, and policy makers interested in estimating the potential impact of targeted public health interventions on a national level.