Purpose: Very few studies have examined cognitive decline in caregivers versus noncaregivers, and only 1 study has examined mediators of such decline. We evaluated the relationship between caregiver status and decline on the digit symbol test (DST; a measure of processing speed, attention, cognitive-motor translation, and visual scanning) and whether this relationship was mediated by depressed mood. Design and Methods: Caregivers for spouses with Alzheimer's disease (n = 122) were compared with demographically similar noncaregiver spouses (n = 117) at study entry (Time 1 = T1), T2 (1 year later), and T3 (2 years after T1). Results: Caregivers had lower DST scores and higher Hamilton depression scores at T1, T2, and T3 than noncaregivers (all p less than 0.05). Hierarchical linear modeling revealed that although caregivers started well below noncaregivers, they experienced a more rapid rate of decline than noncaregivers (p = 0.047). Caregivers declined 4.5 times faster than noncaregivers. Greater depressed mood at T1 (p less than 0.01) and T2 (p less than 0.01) predicted DST decline and mediated DST decline in caregivers vs. noncaregivers. Implications: Depressed mood in caregivers relative to noncaregivers may influence their greater risk for DST decline. This is important because the DST predicts problem solving and everyday functions necessary for independent living and the potential well-being of their care recipients.