Introduction Nicotine exposure via early combustible cigarette smoking can prime the adolescent brain for subsequent cocaine use. However, there is limited evidence whether e-cigarette use, a nicotine delivery system that is increasingly popular among youth, is associated with later cocaine use. We examine the association between e-cigarette use by the age of 14 years and cocaine use by the age of 17 years. Aims and Methods The Millennium Cohort Study is a nationally representative sample of 18 552 9-month-old children born between September 2000 and January 2002 in the United Kingdom. Follow-up interviews and surveys were collected from children and their caregivers at modal ages 3, 5, 7, 9, 11, 14, and 17 years. Our analytic sample included 340 youth who had used e-cigarettes by age 14 years (exposure variable), matched using coarsened exact matching, to 4867 nicotine naive youth on childhood common liability confounders and demographics measured from infancy to age 11. The outcome was cocaine use by the modal age of 17 years. Results Of the 5207 successfully matched youth, 7.6% of adolescent e-cigarette users by age 14 years used cocaine by age 17 years versus 3.1% of non-e-cigarette users. Multivariable logistic regression in the matched sample indicated that e-cigarette use by age 14 years was associated with 2.7 times higher odds of cocaine use by age 17 years (95% CI, 1.75 to 4.28). Conclusions These findings in a UK sample showed that e-cigarette use in early adolescence is associated with higher odds of cocaine use later in adolescence, similar to risks posed by tobacco cigarette smoking. Implications In this large-scale prospective cohort study (n = 5207), youth who had used e-cigarettes by the age of 14 years were matched to nicotine naive youth on childhood common liability confounders and demographics measured from infancy to age 11 years (e.g. school engagement, risk-taking propensity, delinquency, peer and parental smoking, parental educational attainment). After matching, 7.6% of age 14 years e-cigarette users had subsequently used cocaine by the age of 17 years versus 3.1% of non-e-cigarette users. Although e-cigarettes are promoted as a strategy for nicotine-dependent users to reduce the harms of combustible cigarettes, the evidence here suggests that for nicotine naive youth, they may increase the risk of subsequent cocaine use.