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Background A considerable number of the persons living with dementia rely on family members for care and assistance when performing activities of daily living. As a result, caregivers may be at increased risk for mental health problems such as depression, anxiety and caregiver burden. This study examined if and how spiritual coping and stigma-related family stress impacted the associations between the patient activities of daily living impairment and caregiver mental health. Methods Using a longitudinal design, 664 caregivers were assessed at baseline for spiritual coping strategies and family stigma stress, along with patients' instrumental activities of daily living and cognitive functioning. After 12 months, caregivers were assessed for depressive and anxiety symptoms, caregiver burden, and quality of life (physical and mental). Sequential mediation of spiritual coping strategies and stigma-related family stress on the relationship between patient instrumental activities of daily living and caregiver mental health outcomes was examined using the PROCESS macro statistical method. Results Participants had been caring for someone with dementia for an average of 46.4 (SD, 16.9) months and 63% of caregivers were female. There were significant indirect associations between patient instrumental activities of daily living and caregiver anxiety, depression, caregiving burden, and the mental health component of quality of life. Spiritual coping and stigma-related stress mediated these associations (-0.54