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Research has demonstrated disparities in substance use among LGBT+ (lesbian/gay, bisexual, transgender, and nonbinary) youth, which places them at higher risk for behavioral health issues. This three-year longitudinal study compared the initiation, prevalence, and progression of substance use for LGBT+ with straight and cisgender youth in Kansas. Age of initiation was younger, and statistically significant differences were found for LGBT+ students by grade for most substances. Substance use increased as grade level increased for all students; however, disparities generally persisted across grades, with larger percentages of LGBT+ students reporting use. Bisexual and nonbinary students were the most vulnerable groups among participants. Findings provide expanded insight to guide the implementation of prevention strategies to reduce disparities and burden on LGBT+ youth.