OBJECTIVE: Lesbian, gay, and bisexual (LGB) individuals who report greater minority stress (e.g., discrimination) are at an elevated risk for multiple health problems. However, few studies have examined physiological mechanisms that might link minority stress to health. This study tested how cardiovascular and cortisol responses to a laboratory-induced social stressor differed when that stressor contained an additional minority stress component. METHOD: LGB adults (n = 141; 51% male, 49% female) participated in a social stress task in which they were interviewed by a prerecorded confederate. Participants were randomized to receive information that their interviewer held either antigay or progay social/political beliefs. Cardiovascular reactivity and salivary cortisol were assessed at baseline, during the task, and during recovery. RESULTS: All participants experienced significant task-related increases in heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP). However, participants in the antigay condition had greater increases in HR and SBP during the task and smaller decreases in SBP during recovery. Salivary cortisol increased significantly only in the antigay condition. High frequency heart rate variability (hfHRV) was constant throughout the stress task for participants in the progay condition but decreased significantly during the task for participants in the antigay condition. CONCLUSIONS: Minority stress has the potential to affect LGB individuals' health through cardiovascular and endocrine mechanisms. Moreover, its physiological signature may differ from other social stress in ways that have implications for health and emotion regulation more broadly. (PsycInfo Database Record (c) 2021 APA, all rights reserved).