Hospitals play an important role in caring for patients in the current opioid crisis, but data on the outcomes and composition of opioid-driven hospitalizations in the United States have been lacking. Nationally representative all-payer data for the period 1993–2014 from the National Inpatient Sample were used to compare the mortality rates and composition of hospitalizations with opioid-related primary diagnoses and those of hospitalizations for other drugs and for all other causes. Mortality among opioid-driven hospitalizations increased from 0.43 percent before 2000 to 2.02 percent in 2014, an average increase of 0.12 percentage points per year relative to the mortality of hospitalizations due to other drugs—which was unchanged. While the total volume of opioid-driven hospitalizations remained relatively stable, it shifted from diagnoses mostly involving opioid dependence or abuse to those centered on opioid or heroin poisoning (the latter have higher case fatality rates). After 2000, hospitalizations for opioid/heroin poisoning grew by 0.01 per 1,000 people per year, while hospitalizations for opioid dependence or abuse declined by 0.01 per 1,000 people per year. Patients admitted for opioid/heroin poisoning were more likely to be white, ages 50–64, Medicare beneficiaries with disabilities, and residents of lower-income areas. As the United States combats the opioid epidemic, efforts to help hospitals respond to the increasing severity of opioid intoxication are needed, especially in vulnerable populations.