Background: Disclosure of one’s sexual orientation as a sexual-minority (SM) person (i.e., being “out”) may affect HIV-related health outcomes. This longitudinal study examined whether race/ethnicity moderated effects of outness on the plasma kynurenine/tryptophan (KT) ratio, a marker of dysregulated serotonin metabolism due to immune activation that predicts clinical HIV progression. Methods: Participants were African American, Hispanic/Latino, and non-Hispanic White, methamphetamine-using SM men living with HIV (N = 97) who completed self-report scales of outness and SM stress at baseline for a randomized controlled trial of a positive affect intervention. Linear mixed modeling was used to test whether race/ethnicity and experimental condition moderated the association of baseline outness with the KT ratio at baseline, 6, 12, and 15 months controlling for SM stress, sociodemographics, HIV disease markers, and recent stimulant use. Results: The interactions of outness by race/ethnicity and outness by experimental condition on the KT ratio were significant. Greater outness predicted a lower KT ratio over time in non-Hispanic White SM men, but not among SM men of color (MOC). Greater outness predicted a lower KT ratio over time for SM men in the control, but not among those in the intervention arm. Conclusion: Being more out may be protective for non-Hispanic White SM men, but not for their SM MOC peers. Outness mattered for participants who did not receive the positive affect intervention. Findings underscore the potentially different contexts and consequences of outness depending on SM men’s race/ethnicity and whether they received a positive affect intervention.