Depression is the commonest psychiatric disturbance in people with multiple sclerosis (MS), with prevalence higher than in the general population and other chronic diseases. However, accurate assessment of depressive symptoms can be biased by somatic symptoms which are part of both MS and depression. We translated and adapted into Italian the Chicago multiscale depression inventory (CMDI) and assessed its acceptability, internal consistency and test-retest reliability in 213 MS outpatients and 213 individually matched healthy controls. The questionnaire was also tested in 32 people with major depression. Acceptability, internal consistency, and test-retest reliability were good overall. We found greater odds for depressive symptoms in people with MS than healthy controls, with highest odds ratio for somatic symptoms (vegetative subscale). The Italian CMDI is characterized by good acceptability, internal consistency, and test-retest reliability. These findings support the use of the CMDI in Italian subjects with MS to screen for and follow depressive symptoms.