The United States is in the midst of an unprecedented drug epidemic. Illicit use of prescription medicine, predominantly opioids, has become one of the nation's fastest-growing drug problems. We have conducted a retrospective review of prescription opioid fatalities in New York City (NYC) prior to the introduction of a 2013 law intended to curtail prescription drug abuse. Over the 2 years of our study, there were 1286 chemical intoxication fatalities in NYC. Of these, 547 (42.5%) were associated with prescription opioids (6.5/100,000 population). Methadone was most frequently encountered followed by oxycodone. Only 36.7% of decedents had a valid opioid prescription. Of non-opioid medications associated with the prescription opiate deaths, benzodiazepines were the most frequently encountered (68.4%), and alprazolam (35.1%) was most common. Though prescribers have no control over drug diversion they should be cognizant of the urgent public health concern regarding prescription opioid abuse and associated fatalities and attempt to identify doctor shoppers and limit prescription of these potent drugs to those with a legitimate need for pain control. They also need to be aware of the high incidence of fatalities due to combined opioid and benzodiazepine use/abuse and refrain from prescribing them in tandem.