Black women experience disproportional rates of cardiovascular disease (CVD) warranting further exploration of CVD risk factors. Growing evidence suggests acute stress reactivity studies may elucidate the mechanisms driving psychosocial correlates of CVD risks. Race-related stress has been identified as a CVD risk factor among Black women though recent evidence suggests emotions may facilitate these risks. Black women may be vulnerable to shame related to frequent racist experiences. Yet, no study to date has examined racism, shame, and stress reactivity in this population. The current study utilized mixed linear models to test for time and group effects of racism and shame on stress reactivity (e.g., cortisol and C-reactive protein [CRP]) among 34 Black women who completed the Trier Social Stress Test. Tests for two-way interactions (i.e., shame by racism) were also performed. Significant time and group effects were observed for shame and racism on stress reactivity. Black women who experienced greater lifetime racism, stress appraised, but lower racism during the past year, exhibited greater CRP responses. Black women who experienced high levels of shame and racism during the past year and their lifetime demonstrated greater cortisol reactivity. These results prompt further research on racism and shame as CVD risk factors among Black women.