Some researchers have suggested that general self-report depression scales may be inadequate for assessing depression among individuals with Multiple Sclerosis (MS), because many of such items represent MS disease symptoms. However, research has been mixed on this issue: whereas some studies provide support for symptom overlap, others have found opposing evidence. We investigated this issue in two different MS samples with three different strategies. We (1) examined reliable change in depression symptom categories at two time points over three years, (2) assessed the relationship between variables associated with depression and different depression symptom subscales, and (3) assessed the relationship between symptom subscales and physical disability. In each instance we found significant evidence that items meant to assess vegetative symptoms of depression may be influenced by presence of MS disease symptoms or were not associated with other core elements or central correlates of depression. (JINS, 2008, 14, 1057–1062.)