Background Non-medical use (NMU) of prescription opioids is of concern due to the opioid epidemic in the United States. Objective: We examined sex differences in the effect of age of first use of prescription opioids on prescription opioid NMU among 17- and 18-year olds. Methods: The National Monitoring of Adolescent Prescription Stimulants Study (N-MAPSS) recruited youth 10–18 years from 10 United States cities between 2008 and 2011 (n = 11,048). The cross-sectional survey included questions on past 30 day prescription opioid use (10,965 provided responses; 278 age 17 to 18 years who used opioids in past 30 days), with NMU defined as non-oral use and/or use of someone else’s opioids. Nonparametric survival analysis with lifetable estimates was used to examine age at first use. Binomial logistic regression was conducted predicting any NMU, adjusted for covariates. Results: Among 278 youth 17 to 18 years, a significant difference in age of first use between those with MU only and any NMU (p < .0001) was observed. Each one year increase in age resulted in a 33% decrease in the odds of any prescription opioid NMU compared to MU only, after controlling for covariates (Odds Ratio = 0.67, 95% Confidence Interval: 0.47,0.96). Sex differences in age at first use were not observed. Conclusions: Risk of past 30 day prescription opioid NMU decreased by a third for each one year increase in age of first use, after adjustment for other covariates. Use of prescription opioids in young adolescents may need to be limited where possible and researched further.