Background: Nonmedical use of prescription opioids has emerged as a major public health problem during the last decade, but direct measures of incidence and predisposing factors are lacking. Methods: We prospectively measured incidence and antecedents of nonmedical prescription opioid use in The Coronary Artery Risk Development in Young Adults study among 28-40-year-old African- and European-American men and women with no prior history of nonmedical opioid use. Results: Among 3163 participants, 23 reported new nonmedical prescription opioid use in 2000-2001 (5-year incidence 0.7%; 95%CI: 0.4-1.0%). All 23 had previously reported marijuana use (p < 0.001). Five-year incidence was significantly higher among European-American men (OR = 3.3; 95%CI: 1.3-8.3), and among participants reporting a history of amphetamine use (OR = 24; 95%CI: 6.9-83) or medical opioid use for treatment of pain (OR = 8.6; 95%CI: 2.5-30). These associations remained strong when examined among marijuana users and after adjusting for demographics, social factors, and other antecedent substance use. Amphetamine use was the best single predictor of future nonmedical use (sensitivity 87%, specificity 79%). Conclusions: Initiation of nonmedical prescription opioid use is generally rare in 28-40-year-old adults, but is observed to be more common with a previous history of substance abuse and legal access to opioids through prescription by a physician. © 2006 Elsevier Ireland Ltd. All rights reserved.