E-cigarette use may be associated prospectively with subsequent cannabis use among U.S. adolescents. However, it remains unclear whether this association differs by individual mental health status. This longitudinal study examines effect modifications by mental health status. The first 4 waves (2013-2017) of the Population Assessment of Tobacco and Health study were analyzed in 2020. Adolescents (aged 12-17 years) who reported never using cannabis at baseline waves were included. Waves 1-3 were each considered as baseline for their 12-month follow-up waves. Generalized estimating equations were used to evaluate the effect modification of internalizing mental health and externalizing mental health problems on the associations between baseline past 30-day e-cigarette use and past 30-day cannabis use at follow-up, controlling for individual characteristics and state recreational cannabis laws. Baseline e-cigarette use was significantly associated with cannabis use at follow-up (AOR=4.81, 95% CI=2.93, 7.90). Adolescents with high severity of internalizing mental health/externalizing mental health problems were significantly more likely to initiate cannabis use. However, current e-cigarette users who reported high severity of internalizing mental health symptoms were less likely to initiate cannabis use (AOR=2.51, 95% CI=0.92, 6.83) than those who reported low severity of internalizing mental health problems (AOR=8.84, 95% CI=4.19, 18.65). There were no differences by the severity of externalizing mental health problems. Baseline e-cigarette use and endorsement of severe internalizing mental health/externalizing mental health problems were significantly associated with subsequent cannabis use among U.S. adolescents. Efforts to reduce youth vaping and improve youth mental health could help curb cannabis initiation. Tailored interventions may be warranted for e-cigarette‒using adolescents with internalizing mental health problems.