There is minimal evidence from epidemiological studies on how e-cigarette use is related to health indices in adolescence. We hypothesized that e-cigarette use would be associated with asthma, controlling for demographics and cigarette smoking. The hypothesis was tested with cross-sectional data from a statewide sample of school students. Surveys were administered in classrooms in 2015 to adolescents in 33 high schools throughout the State of Hawaii. The sample (N = 6089) was 50% female and mean age was 15.8 years. Data were obtained on demographics; ever use and current (past 30 days) use of e-cigarettes, combustible cigarettes, and marijuana; ever being diagnosed with asthma; and currently having asthma. Multinomial regression examined the association between e-cigarette use and asthma controlling for cigarette smoking, marijuana use, and six demographic covariates. Current e-cigarette use was associated with currently having (vs. never having) asthma (adjusted odds ratio [aOR] = 1.48, CI 1.26–1.74) and with previously having (vs. never having) asthma (aOR = 1.22, CI 1.07–1.40). This was independent of cigarette smoking, marijuana use, and other covariates. Smoking and marijuana were nonsignificant in the multivariate analysis. Blacks, Native Hawaiians, other Pacific Islanders, and Filipinos had higher rates of asthma compared with Asian Americans and Caucasians. We conclude that e-cigarette use by adolescents is independently associated with asthma. This finding is consistent with recent laboratory research on pulmonary effects from e-cigarette vapor. Implications for public health should be considered.