We examined the effect of negative affect on changes in stimulated secretion of cytokines by blood monocytes and determined whether insulin resistance (IR), as indexed by the Homeostasis Model Assessment (HOMA), moderated these associations in 58 healthy men (aged 18-65 years). Blood samples and ratings of negative affect were collected at rest and 15min following subjects' participation in the Anger Recall Interview (ARI). Assessment of lipopolysaccharide (LPS)-stimulated secretion of IL-1beta, IL-6, and TNF-alpha was accomplished by ELISA of supernatant. Regression models controlling for age, body mass index, and race/ethnicity revealed that higher HOMA-IR values were associated with larger stress-induced increases in IL-1beta and TNF-alpha (p<.05). Furthermore, arousal of negative affect during the ARI was differentially associated with stress-induced changes in stimulated secretion of TNF-alpha and IL-6 as a function of HOMA-IR (p<.05). Increases in stimulated cytokine secretion were associated with arousal of negative affect, but only among men with higher HOMA-IR values. Among men with lower HOMA-IR values, arousal of negative affect was associated with diminished cytokine secretion. Collectively, these data suggest that the HOMA-IR moderates the impact that arousal of negative affect has on the ability of blood monocytes to secrete inflammatory cytokines in response to LPS. Stress-induced increases in cytokine secretion among high HOMA-IR men are consistent with the role of inflammation in cardiovascular disease, hypertension, type 2 diabetes as well as the metabolic syndrome and underscore the relevance of negative affect in the etiology of these inflammatory conditions.