The aim of this study was to examine, within the context of a treatment study, the relative contributions of depression and neuropsychological performance on patient ratings of cognitive functioning in a cohort of 58 moderately-depressed multiple sclerosis (MS) patients. All participants were randomized to one of three 16-week conventional treatments for depression. Assessments were conducted pre- and post-treatment using: (1) Cognitive Function subscale of the Multiple Sclerosis Quality of Life-54 (MSQOL-54) to evaluate subjective cognitive impairment (SC), (2) Beck Depression Inventory (BDI), and (3) a neuropsychological index score (NP). Prior to treatment, 8% of the variance in SC was explained by NP, whereas 14% of the variance was explained by BDI, above and beyond NP. At post-treatment, patients were classified as 'responders' (BDI < 11) and 'non-responders' (BDI > or = 11). Among those participants classified as 'responders', NP accounted for 39% of the variance in SC, and BDI did not significantly predict SC. The results of this study suggest that depression may influence subjective reports of cognitive impairment, but these reports may not be reliably related to objective neuropsychological performance. Furthermore, patients may be more accurate reporters of their cognitive impairment after successful treatment for depression, suggesting that depression decreases the accuracy of patient reported cognitive impairment.