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To examine the relation of illness intrusiveness and illness uncertainty to psychological distress in patients with multiple sclerosis (MS).Participants were recruited from regional support groups and local neurologists. Participants completed self-report measures of illness intrusiveness, illness uncertainty, and psychological distress. Disease status was assessed by administration of a mental status exam and an index of ambulation.The sample included 78 (55 women, 23 men) individuals diagnosed with MS.The Symptom Checklist—90—Revised Global Severity Index.Hierarchical regression analyses indicated that illness intrusiveness and illness uncertainty independently predicted adjustment problems above and beyond demographic and illness variables. No mediator or moderator relationships were found for illness intrusiveness.Psychological appraisals of illness are salient predictors of adjustment even after statistically controlling for the influence of age, education, and objective indices of physical and cognitive impairment.