BACKGROUND Although the relationship between smoking and depression has been well-established, little is known about the association between use of e-cigarette and depression, particularly among youth and young adults. This study proposes that e-cigarette dependence, rather than simply use, serves as a potential stressor and may interact with pre-existing vulnerabilities to contribute to depression in youth, consistent with the diathesis-stress theory. This study examines the longitudinal association of vaping dependence and vaping frequency on depression symptoms among youth and young adults who have never smoked cigarettes. METHODS People who used e-cigarettes in the past month who reported never smoking a cigarette (N=1,226) aged between 16 and 25 years were followed longitudinally every 3 months for up to 1 year beginning in 2020. The Penn State E-Cigarette Dependence Index at time t was used to predict depression symptoms assessed using the Center for Epidemiologic Studies Depression Scale at time t+1. RESULTS A total of 32.1% reported vaping in the past month with the Penn State E-Cigarette Dependence Index score (M=8.5) and a Center for Epidemiologic Studies Depression Scale score (M=15.8). Higher vaping dependence scores were significantly associated with increased depression symptoms scores at follow-up among youth and adults (β=0.08; 95% CI=0.01, 0.15), controlling for baseline depression symptom scores and covariates. Although vaping dependence was highly associated with vaping frequency level, no significant association between the frequency of vaping and depression was found (β= -0.33; 95% CI= 1.21, 0.54). CONCLUSIONS These results are consistent with the diathesis-stress model of the relationship between substance use and depression. Vaping dependence but not vaping frequency was associated with increased depressive symptoms among people who never smoked cigarettes.