Objective To examine the longitudinal associations between caregiver strain and patients' clinical and psychosocial characteristics as well as caregivers' psychosocial characteristics. Methods At 4-month intervals during the 12 months study period, longitudinal data on caregiver strain and patient and caregiver factors potentially associated with caregiver strain were collected from 126 couples, who participated in a randomised controlled trial on the effectiveness of case management in amyotrophic lateral sclerosis (ALS). Caregiver strain was assessed with the Caregiver Strain Index (CSI). Patient and caregiver factors included sociodemographic characteristics, distress, coping style and perceived quality of care, as well as the patient's functional status and emotional functioning. Multilevel regression analyses were performed. Results Caregiver strain increased significantly during the study period (β=0.315 points/months, p<0.001) and was significantly associated with patient time-dependent factors functional status (β=?0.131 points/months, p<0.001) and emotional functioning (β=0.022 points/months, p=0.03), and caregiver time-dependent factors passive coping style (β=0.152 points/months, p=0.03), symptoms of anxiety (β=0.186 points/months, p<0.001) and perceived quality of care for the caregiver (β=?0.452 points/months, p<0.001). Conclusions Our study has identified that apart from the patient's physical disability and emotional well-being, a passive coping style of the caregiver, increased symptoms of anxiety and feeling less supported by the ALS-team impact on caregiver strain. The multidisciplinary teams involved with the care of patients with ALS need to be aware of these factors and increase their attention for the caregiver. This will help guide the development of evidence-based supportive interventions that focus on caregiver's coping style and avoiding distress.