Background: E-cigarette (ECIG) use has increased substantially in the past decade. Co-use of alcohol and ECIGS may have serious consequences in adolescents. Objectives: To evaluate the association of e-cigarettes (ECIGs) with alcohol use in adolescents. Methods: Searched databases included PubMed, EMBASE, CINAHL, PsycINFO, Web of Science, and gray literature. Studies were included if they contained a non-E-cigarette group (NON-ECIG), an ECIG group, detailed rates of alcohol use, binge drinking, or drunkenness and included adolescents. Two independent reviewers extracted data using MOOSE guidelines. Evidence quality across studies was assessed using Cochrane GRADE methodology. Summary effects of ECIG vs. NON-ECIG use on any alcohol use and a composite of binge drinking/drunkenness were calculated using a random-effects model. Results: 28 of 3768 initially identified studies were included: 25 cross-sectional, 3 cohort studies, N = 458,357 total subjects (49.6% females). Pooling of data showed that ECIG users had a higher risk for any alcohol use compared to NON-ECIG users (Odds Ratio/OR 6.62, 95% confidence interval/CI 5.67-7.72) and a higher rate of binge drinking/drunkenness compared to NON-ECIG users (OR 6.73, 95% CI 4.5 − 10.07). The subset of high school ECIG users had higher rates of alcohol use (OR 8.17,) and binge drinking/drunkenness (OR 7.98, 95% CI 5.98-10.63) compared to NON-ECIG users. Conclusion: ECIG users had a higher risk of alcohol use and binge drinking/drunkenness compared to NON-ECIG users. Our findings indicate that interventions to reduce ECIG use should be coupled with measures to reduce alcohol use in adolescents.