Prior research suggests that the Type A behavior pattern, Cook and Medley Hostility (Ho) scores, and Total Serum Cholesterol (TSC) are positively associated with physiological changes to behavioral stressors. The objective of the present study was to determine whether TSC interacts with the Type A behavior pattern and hostility to affect cardiovascular and neurohormonal responses to a mental arithmetic task (MATH). For Type A individuals, elevated TSC was associated with larger catecholamine and cortisol responses to MATH. In contrast, for Type B subjects, cholesterol was negatively associated with neurohormonal responses. The interaction between Ho score and TSC predicted a similar pattern of responses whereby, in high hostile men only, TSC was positively associated with MATH-induced changes in catecholamines and heart rate. While the mechanisms responsible for the differences in the lipid-reactivity association as a function of coronary-prone behavior measures remain to be elucidated, this differential association may play a role in the heightened risk of coronary disease among hostile Type A men.