There is a large body of experimental evidence in research animals and in vitro models that opioids suppress the immune system. If this effect occurs in acute human disease, then patients cared for in Intensive Care Units (ICUs) would be a particularly vulnerable population. ICU patients have the most severe forms of acute infection, have the greatest risk of acquiring new infections in the hospital, and are exposed to high doses of opioids for long periods of time. We review the epidemiology of ICU infections and the pharmacoepidemiology of opioid use in critically ill patients. We critique the limited human research examining the relationship between opioids and infection and make recommendations on designing future clinical studies that could close the knowledge gap about the true hazards of opioid use in hospitalized patients.