Aims To examine non-medical use of prescription opioids (NMUPO) patterns during the transition from adolescence to adulthood, and assess individual characteristics and other substance use behaviors associated with longitudinal patterns of NMUPO. Design Nationally representative samples of high school seniors in the United States (wave 1: modal age 18 years) were followed longitudinally across three biennial follow-up waves (waves 2, 3 and 4: modal ages 19/20, 21/22 and 23/24 years). Setting Data were collected via self-administered questionnaires to high school seniors and young adults. Participants The longitudinal sample consisted of 27?268 individuals in 30 cohorts (high school senior years 1976?2005) who participated in all four waves. Measurements Self-reports of NMUPO and other substance use behaviors. Findings Approximately 11.6% [95% confidence interval (CI)?=?11.2%, 12.0%] of the sample reported past-year NMUPO in at least one of the four waves. Among those who reported past-year NMUPO in at least one wave, 69.0% (67.6%, 70.4%), 20.5% (19.3%, 21.7%), 7.8% (7.1%, 8.6%) and 2.7% (2.3%, 3.1%) reported NMUPO at one, two, three and four waves, respectively. Several wave 1 variables were associated with greater odds of multiple waves of NMUPO and individuals who reported more waves of NMUPO had greater odds of other substance use behaviors. Conclusions Although most non-medical use of prescription opioids among 18-year-olds in the United States appears to be non-continuing, approximately one-third of the sample reporting non-medical use of prescription opioids appear to continue use beyond age 18 and have elevated odds of other substance use behaviors at ages 23/24.