Research has shown that several variables influence the burden of primary caregivers of cancer patients staying at home in the palliative phase, but the associations between these variables have hardly been explored. The aim of this study was to examine the associations of theory-driven variables with the caregivers' burden by means of path analysis. The sample consisted of 96 caregivers of cancer patients in the palliative phase staying at home recruited from a hospital trust in Norway. The dimensions of burden from the Caregiver Reaction Assessment, namely self esteem, lack of family support, impact on finances, and impact on daily schedule, were used as the dependent variable. The following independent variables were tested in the models: the patients' levels of pain, fatigue, and nausea; and the caregivers' physical quality of life, anxiety and depression, and social support. The Partial Least Squares approach to structural equation modelling was used for the path analysis. Model 1 shows the direct associations between the independent variables and the dependent variable, explaining 16% of the variance in caregiver burden. Model 1 supports the finding that only caregivers' depression has a direct significant association with caregiver burden, and shows further that the effects of the other independent variables on burden are mediated through depression. In Model 2, anxiety and depression are mediating factors between three other independent variables and caregiver burden, and 12% of the variance is explained. Model 2 supports none of the independent variables as antecedents of burden. Testing of the models suggested that caregivers' depression was the main factor associated with caregiver burden, but also an important mediator of indirect associations of indirect associations of caregivers' anxiety and physical health.