Background: Benzodiazepines are used to relieve symptoms of anxiety, panic attacks, and seizures and are safe and effective when taken as prescribed and directed. However, benzodiazepines depress central nervous system (CNS) activity and, when combined with other drugs that depress CNS activity such as alcohol or opioid pain relievers, may present serious or even life-threatening problems. Concerns exist about the increasing number of patients prescribed both benzodiazepines and opioids and about serious complications arising from the use of benzodiazepines with alcohol. Methods: Drug Abuse Warning Network (DAWN) data on drug-related emergency department (ED) visits from 2005 to 2011 were combined to ensure adequate sample size. Logistic regression was used to examine the association between ED visit outcome and benzodiazepine combinations with opioids and alcohol, patient age, gender, and the year in which the visit occurred. Results: During the 7 years from 2005 to 2011, almost a million (an estimated 943,032) ED visits involved benzodiazepines alone or in combination with opioid pain relievers or alcohol and no other substances. The predicted risk of a more serious outcome (hospitalization or, rarely, death in the ED rather than treatment and release), was greater than 20% for all age categories for benzodiazepines alone. Combinations of benzodiazepines with opioid pain relievers or alcohol were associated with a 24 to 55% increase in the predicted risk of a more serious outcome compared with benzodiazepines alone. Increasing age was associated with increasing predicted risk of a more serious outcome for visits involving benzodiazepines alone or in combination with opioid pain relievers or alcohol and no other substances. Conclusion: ED visits involving benzodiazepines alone pose a significant risk of hospitalization. Combining benzodiazepines with opioid pain relievers or alcohol significantly increases the risk of serious ED visit outcome for all age groups. Further, older patients experience increased risk of a serious outcome, even for visits involving benzodiazepines alone. Together, these facts suggest that individuals are at risk and that the baseline risks are high enough to suggest a public health concern.