Our objective was to assess the impact of personal, situational and patient characteristics on mood, and changes over time, among ALS caregivers. Seventy-one patient-caregiver pairs were interviewed once and 51 (72%) monthly until endpoints of death or tracheostomy for long-term mechanical ventilation (LTMV). Depressive symptoms and DSM-IV disorders, coping strategies, caregiver burden, satisfaction with care-giving, and patient disease severity were assessed. At baseline, 13% of caregivers had major depression, and 10% had minor depression. Rates declined at last visit before death or LTMV (median interval three months), as did depressive symptoms. Correlates of caregiver depression included reliance on avoidance, perceived burden, fatigue, and feeling that the patient was critical and unappreciative. Half of the 14 caregivers of patients who planned LTMV were depressed at baseline, declining to 8% at endpoint, versus 16% (9/57) among caregivers of patients who died, declining non-significantly to 11%. While few personal or situational factors were correlated with caregiver distress, patients' plans and degree of supportiveness influenced caregiver mood. Verbal comments of caregivers clarified the distinction between sadness and psychiatric depression. The high baseline rate of depression among caregivers of patients who planned tracheostomy decreased as caregivers instituted major changes in patient care or personal counseling.