Aims The present study examined the associations between early onset of non-medical use of prescription drugs (NMUPD) (i.e. sedatives, tranquilizers, opioids, stimulants) and the development of prescription drug abuse and dependence in the United States. Design Data were collected from structured diagnostic interviews using the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Alcohol Use Disorder and Associated Disabilities Interview Schedule: Diagnostic and Statistical Manual version IV (DSM-IV). Setting National prevalence estimates were derived from the 2001?2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC, n = 43 093). Participants A nationally representative cross-sectional sample of civilian non-institutionalized adults aged 18 years or older in the United States, of whom 52% were women, 71% white, 12% Hispanic, 11% African American, 4% Asian and 2% Native American or of other racial background. Findings A higher percentage of individuals who began using prescription drugs non-medically at or before 13 years of age were found to have developed prescription drug abuse and dependence versus those individuals who began using at or after 21 years of age. Multivariate logistic regression analyses indicated that the odds of developing any life-time prescription drug abuse among non-medical users was reduced by approximately 5% with each year non-medical use was delayed [adjusted odds ratio (AOR) = 0.95, 95% CI = 0.94, 0.97], and that the odds of developing any life-time prescription drug dependence were reduced by about 2% with each year onset was delayed (AOR = 0.98, 95% CI = 0.96, 1.00) when controlling for relevant covariates. Conclusions The results of this study indicate that early onset of NMUPD was a significant predictor of prescription drug abuse and dependence. These findings reinforce the importance of developing prevention efforts to reduce NMUPD and diversion of prescription drugs among children and adolescents.