OBJECTIVES Physicians are a key stakeholder in the epidemic of prescription opioid abuse. Therefore, we assessed their knowledge of opioid abuse and diversion, as well as their support for clinical and regulatory interventions to reduce opioid-related morbidity and mortality. MATERIALS AND METHODS We conducted a nationally representative postal mail survey of 1000 practicing internists, family physicians, and general practitioners in the United States between February and May 2014. RESULTS The adjusted response rate was 58%, and all physicians (100%) believed that prescription drug abuse was a problem in their communities. However, only two-thirds (66%) correctly reported that the most common route of abuse was swallowing pills whole, and nearly one-half (46%) erroneously reported that abuse-deterrent formulations were less addictive than their counterparts. In addition, a notable minority of physicians (25%) reported being "not at all" or "only slightly concerned" about the potential for opioid diversion from the licit to the illicit market when this practice is common at all levels of the pharmaceutical supply chain. Most physicians supported clinical and regulatory interventions to reduce prescription opioid abuse, including the use of patient contracts (98%), urine drug testing (90%), requiring prescribers to check a centralized database before prescribing opioids (88%), and instituting greater restrictions on the marketing and promotion of opioids (77% to 82%). Despite this, only one-third of physicians (33%) believed that interventions to reduce prescription opioid abuse had a moderate or large effect on preventing patients' clinically appropriate access to pain treatment. DISCUSSION Although physicians are unaware of some facets of prescription opioid-related morbidity, most support a variety of clinical and regulatory interventions to improve the risk-benefit balance of these therapies.