<p>Transgender and gender-expansive young people, ages 13–24 years, experience disproportionate HIV risk yet are among those with the lowest US PrEP uptake rates (&lt; 10%). Factors influencing PrEP outcomes for this population are poorly understood. This study examines the effects of gender minority stressors, gender affirmation, and heavy substance use on their PrEP outcomes using data from the CDC’s 2018 START study (<i>N</i> = 972). A conceptual model integrating the gender minority stress and gender affirmation models was developed, mapping relevant START items onto it. Structural equation modeling (Mplus-8.9) was used to examine factors related to their PrEP intentions. Most participants were 18–24 (68%), trans-female (46%), white (45%), and reported heavy substance use (40%). Medical discrimination increased internalized transphobia (b = 0.097, SE = 0.034, <i>p</i> = 0.005) and perceived stigma (b = 0.087, SE = 0.034, <i>p</i> = 0.010). Family rejection increased perceived stigma (b = 0.181, SE = 0.032, <i>p</i> &lt; 0.001) and heavy substance use (b = 0.260, SE = 0.053, <i>p</i> &lt; 0.001). Perceived stigma also increased heavy substance use (b = 0.106, SE = 0.037, <i>p</i> = 0.004). Perceived stigma (b=-0.085, SE = 0.027, <i>p</i> = 0.002) and heavy substance use (b=-0.161, SE = 0.031, <i>p</i> &lt; 0.001) decreased PrEP intentions, while gender affirmation increased them (b = 0.045, SE = 0.019, <i>p</i> = 0.020). A 1-point increase in gender affirmation reduced heavy substance use risk by -0.179 (SE = 0.030, <i>p</i> &lt; 0.001) in the presence of family rejection and by -0.074 (SE = 0.041, <i>p</i> = 0.074) when perceived stigma was present. This study underscores heavy substance use as a potential barrier to PrEP uptake for transgender/gender-expansive youth. Future research could explore how gender affirmation acts as a protective factor against the negative impact of family rejection and perceived stigma on heavy substance behaviors among these populations.</p>