Objective: We evaluated the effect of the cortisol (CORT) to high sensitivity C-reactive protein (hsCRP) ratio on stress-induced negative affect (NA) reactivity and whether the association was moderated by depressive symptom severity and gender. The CORT/CRP ratio was used to evaluate the integrity of the negative feedback loop between the hypothalamic-pituitary-adrenal axis and inflammatory response system. Method: Basal CORT and hsCRP levels were measured in fasting blood samples from 198 medication-free and nonsmoking healthy men and women. Depressive symptom severity was assessed using the Hamilton Rating Scale for Depression (HAMD). NA ratings were collected at baseline and at the completion of the laboratory stressors, the Anger Recall Interview (ARI) and reading. Results: Adjusting for potential confounders and baseline NA, analysis revealed a significant relationship between CORT/CRP ratio and NA reactivity to ARI as a function of depressive symptom severity. Simple effects revealed that for participants with high HAMD, decreasing CORT/CRP ratio, suggestive of an insufficient CORT release relative to higher hsCRP, predicted increasing stress-induced NA reactivity. For participants with low HAMD, the CORT/CRP ratio failed to predict NA reactivity. Gender did not moderate the joint effect of depressive symptom severity and the CORT/CRP ratio on stress-induced NA reactivity. Conclusions: This is the first study to document that a premorbid dysregulation of the neuro-immune relationship, characterized by an insufficient release of CORT in conjunction with higher CRP, plays a role in stress sensitivity, and specifically NA reactivity, in individuals with elevated levels of depression symptoms.