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Life stress and coping responses jointly contribute to psychological adjustment in many chronic illness populations, but their significance in multiple sclerosis (MS) has not been extensively investigated. Physical disability, cognitive status, negative life stress, coping strategies, and depressive symptoms were prospectively assessed in 27 adults with definite or probable MS. Of the original subjects, 22 provided two additional assessments at 6-month intervals. After accounting for cognitive status and physical disability, life stress was positively correlated with current as well as future depressive symptoms; the prospective relationship was replicated within the second pair of prospective data waves. Escape avoidance was the only coping strategy that added to the prediction of future mood symptoms, but this was not replicated. Results suggest that MS-related depressive symptoms are a function of prior disease-related impairment, life stress, and possibly escape avoidance coping....