Sexual minority (SM) adults (those who are lesbian, gay, or bisexual) consistently report more health problems compared to heterosexuals, and they tend to experience excess social stress. Although numerous studies have established links between social stress and clinical outcomes in SM adults, few studies have examined biological factors that may help explain how social stress leads to health disparities among SM adults. We used data from the Midlife in the United States Study (MIDUS) to examine whether two inflammatory markers that have been commonly associated with social stress—C-reactive protein (CRP) and interleukin-6 (IL-6)—differed by sexual orientation and whether any differences were explained by perceptions of discrimination. Participants self-identified as heterosexual (n = 1956) or lesbian, gay, or bisexual (n = 81). After controlling for age, gender, race, and education, SM individuals had higher CRP and IL-6 than heterosexuals on average and these differences were partially explained by perceptions of discrimination. Implications for inflammatory pathways as mechanisms related to SM health disparities and discrimination are discussed.