BACKGROUND: To determine the effects of depressive symptom severity on the circulating soluble adhesion molecule response to an acute exercise challenge in patients with heart failure (HF) compared with control subjects. METHODS: Thirty-eight male HF patients and 19 male control subjects (mean age +/- SEM: 55.5 +/- 1.9) completed the Beck Depression Inventory (BDI) before undergoing a moderate 20-minute bicycle exercise at approximately 65% to 70% VO(2peak). Plasma levels of the soluble adhesion molecules P-selectin (sP-selectin) (sCD62P) and soluble intercellular adhesion molecule-1 (sICAM-1) were determined immediately before and after and 10 minutes after exercise. RESULTS: Higher BDI scores moderated greater increases in sP-selectin levels in response to exercise over time in HF patients as compared with control subjects [F(1.8/84.5) = 3.25, p = .05]. Post hoc testing revealed that in HF patients, but not in control subjects, higher BDI scores were significantly associated with greater increases in sP-selectin levels over time in response to exercise [BDI by exercise interaction: F(1.6/49.6) = 5.67, p = .010]. Also, in HF patients, but not in control subjects, higher BDI scores were associated with higher sP-selectin levels at pre-exercise and postexercise time points [main effect BDI: F(1/31) = 4.86, p = .035]. CONCLUSIONS: Our findings suggest that in male HF patients with increasing depressive symptom severity, levels of the adhesion molecule sP-selectin are higher before and after exercise and have greater increases in response to exercise. This could have implications for acute coronary syndromes associated with exercise and thereby may impact mortality.