ABSTRACT Background: Traveling to meet sexual partners and substance use are associated with increased risk of infectious disease. It is important to understand what factors may increase substances use or increased infection transmission risk (IITR) sexual behaviors among rural LGBTQ+ individuals. Objective: This study investigates substance use and sexual behaviors associated with increased infection transmission risk among rural LGBTQ+ individuals, and how these are associated with relationship type (friends or romantic partners) and travel distance. Methods: Participants (18 years+, identify as LGBTQ+, and provided a $25 gift card) were recruited from Illinois (25 counties), in 2021. Data included demographics, sexual and drug use behaviors, and assessed how these behaviors varied by relationship type and distance traveled (e.g. when meeting friends out-of-state). Results: The 398 participants were 79.1% White and 12.3% Black. By orientation, 29% heterosexual, 36% gay/lesbian, and 35% bisexual/other. By identity, 43% cisgender male, 51% cisgender female, and 6% genderqueer/other. Alcohol use while visiting out-of-state friends was more frequent among transgender (vs cisgender men; OR = 9.686, 95% confidence interval = 2.123-44.19), and individuals traveling > 1/month (all p < .050). Infection-related sexual behaviors while visiting out-of-state romantic partners was more frequent among prescription medication misuse (all p < .050) and traveling > 1/week (vs < 1/month; OR = 3.399, 95% CI = 1.037-11.144). Conclusion: This study of rural LGBTQ+ identified that alcohol use was associated with travel to visit out-of-state romantic partners, and prescription medication misuse increased infection-related sexual behavior during out-of-state travel. Health professionals can develop substance use and increased infection transmission risk sexual behavior interventions on gender minority groups in rural areas and target those who are traveling.