Background: Although research on adolescent e-cigarette use is growing, several questions remain unanswered, including the timing of initiation and the co-occurrence with initiation of other substances. The current study longitudinally evaluated the risk for initiation of e-cigarettes and examined associations with this risk and initiation of other substances (alcohol, traditional tobacco products, and marijuana). Methods: 141 youth from a single high school were in 9th and 10th grade at the initial data collection. Data were collected annually for the following two years. Rates of initiation were calculated. Cross-lagged panel models estimated how prior initiation of e-cigarette use affected the risk for initiation of other substances and vice-versa. Results: Risk for initiation of e-cigarettes was comparable across the two years. Youth were most at risk for having used alcohol at baseline. As youth aged through high school, they were most at risk for initiation of e-cigarettes relative to other substances. There is preliminary evidence that endorsement of alcohol use at baseline increased the risk for initiation of e-cigarettes one year later. Conclusions: Rates of e-cigarette initiations increased throughout the two-year period. These preliminary findings support the notion that efforts to prevent initiation of e-cigarettes should target adolescents who have used alcohol.