Depression is the most frequent negative health outcome among informal caregivers. The aims of the current study were (a) to assess the level of depression, (b) to explore associations among care recipients' characteristics, caregivers' characteristics, situational factors, and depression among Ultra-Orthodox Jewish (UOJ) caregivers. A total of 112 (44 men and 68 women) UOJ primary caregivers of frail older adults were interviewed face-to-face in their homes, using valid and reliable measures. Participants reported a notable depressive symptomatology. Three variables emerged as significant predictors of caregiver depression: higher external control (chance), being a spouse, and lower levels of social support. External locus of control, being a spouse, and social support were found to be highly important factors for explaining depression among UOJ caregivers. Resources should be allocated to target spousal caregivers with lower levels of social support and a greater sense of external locus of control in order to alleviate their depressive symptomatology.