We studied the psychophysiology of soluble intercellular adhesion molecule-1 (sICAM-1) in 25 apparently healthy middle-aged men who underwent an acute psychosocial stressor three times with one week apart. Measures of the biological stress response were obtained at week one and three. The magnitude of the sICAM-1 stress response showed no habituation between individual visits. At week one, cognitive stress appraisal independently predicted integrated sICAM-1 area under the curve (AUC) between rest, immediately post-stress, and 45 min and 105 min post-stress (beta=0.67, p=0.012, deltaR(2)=0.41). Diastolic blood pressure AUC (beta=-0.45, p=0.048, deltaR(2)=0.21) and heart rate AUC (beta=0.44, p=0.055, deltaR(2)=0.21) were independent predictors of sICAM-1 AUC at week three. Adjustment for hemoconcentration yielded a decrease in sICAM-1 levels from rest to post-stress (p<0.001). Stress responsiveness of plasma sICAM-1 was predicted by stress perception and hemodynamic reactivity and affected by stress-hemoconcentration but unrelated to cortisol reactivity and not readily adapting to repeated stress.