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After completing questionnaires assessing stressful life events, perceived stress, and negative affect, 394 healthy Ss were intentionally exposed to a common cold virus, quarantined, and monitored for the development of biologically verified clinical illness. Consistent with the hypothesis that psychological stress increases susceptibility to infectious agents, higher scores on each of the 3 stress scales were associated with greater risk of developing a cold. However, the relation between stressful life events and illness was mediated by a different biologic process than were relations between perceived stress and illness and negative affect and illness. That these scales have independent relations with illness and that these relations are mediated by different processes challenges the assumption that perceptions of stress and negative affect are necessary for stressful life events to influence disease risk.