The relationship between disability and depression was studied in 188 patients with clinically definite multiple sclerosis (MS). Patients were administered the Zung Self-Rating Depression Scale, Ways of Coping, Uncertainty of Illness Scale, and Hope Scale during their regular clinic appointments. Their current level of disability was rated by the attending physician using the Expanded Disability Status Scale. Even when the depression measure was corrected for items overlapping with other symptoms or consequences of MS, depression was correlated with disability. Depression was also correlated with an array of psychological variables, including uncertainty concerning ones illness, hope, and the use of various emotion-centered, though not problem-centered coping strategies. Multiple regression analyses revealed that none of these psychological correlates mediated or moderated the relationship between disability and depression. Instead, disability, uncertainty, hope, and emotion-centered coping were significant independent predictors of depression, together accounting for approximately 40% of the variance in patients' self-reported depression. The relationship between disability and depression in MS is usually interpreted as evidence that depression is psychogenic and reactive to the demands and limitations of this disease. The demonstration that this relationship is not diminished when an array of potentially intervening psychological variables are included in the analysis raises questions concerning the validity of this interpretation.