Sexual and gender minorities assigned female at birth (i.e., sexual minority women, transgender men, and gender diverse [SMW TGD] individuals) experience disproportionately high rates of anxiety, depression, and substance use problems. Romantic relationship involvement has been shown to be beneficial to mental health and substance use among sexual and gender minorities. However, few studies have explored the impact of relationship quality on mental health, or if high relationship quality can reduce the negative impact of minority stress on well-being in this population. The present study examined within-persons associations of romantic relationship quality with symptoms of anxiety and depression, and alcohol and cannabis use problems among SMW TGD individuals in romantic relationships, and tested relationship quality as a moderator of associations of minority stress with mental health and substance use. Participants were 213 SMW TGD individuals (mean age: 20.63; 70.9% cisgender women, 7.5% transgender men, and 19.2% gender diverse). Within-persons, higher relationship quality was associated with better mental health and substance use outcomes. Relationship quality at the between-persons level moderated the within-persons association of internalized heterosexism with depression, and of microaggressions with cannabis use problems. No other interaction effects were significant. The within-persons associations found in this study lend important support to relationship interventions based on theories that improvements in romantic relationship quality will result in improved well-being over time. Results can inform relationship education interventions to reduce mental health and substance use disparities in SMW TGD communities. (PsycInfo Database Record (c) 2022 APA, all rights reserved).