Cognitive impairment and depressed mood are common symptoms in multiple sclerosis (MS), which significantly impact patients' role functioning and quality of life. Cross-sectional studies indicate a modest association between cognitive impairment and depressive symptoms in MS. Longitudinal studies show inconsistent results but provide some data indicating a relationship between increasing global cognitive decline and increasing depressive symptoms over time. Establishing whether such a relationship exists represents an important first step in understanding the temporal nature of that relationship along with any treatment implications. The current study investigated this relationship by using the adjusted difference between a demographic estimate of premorbid intellectual functioning (Barona) and a performance measure of current intellectual functioning (Shipley Institute of Living) to capture long-term global cognitive decline in MS patients. Degree of global cognitive decline was then related to a self-report measure of mood, evaluative, and vegetative depression symptoms (Chicago Multiscale Depression Inventory). Global cognitive decline accounted for 5% of the variance in mood-evaluative symptoms but none of the variance in vegetative symptoms. When groups experiencing moderate, mild, and no global cognitive decline were compared on depression symptom subscales, MS patients experiencing moderate cognitive decline reported significantly higher mood and evaluative, but not vegetative, depressive symptoms than MS patients with stable cognitive functioning.