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Abstract: Background: The aim was to determine the risk of Mood Disorders (MD), particularly Bipolar Disorders (BD), in Multiple Sclerosis (MS) using standardized psychiatric diagnostic tools. Methods: Case–control study. Cases: 201 consecutive-patients with MS. Controls: 804 sex- and age-matched subjects without MS, randomly selected from a database concurrently used for an epidemiological study on the MD prevalence in the community. Psychiatric diagnoses according to DSM-IV were determined by physicians using structured interview tools (ANTAS-SCID). Results: Compared to controls, MS patients had a higher lifetime prevalence of DSM-IV Major Depressive Disorders (MDD; P<0.0001), BD I (P=0.05), BD II (P<0.0001) and Cyclothymia (P=0.0001). As people with MS had a higher risk of depressive and bipolar spectrum disorders, ratio MDD/bipolar spectrum disorders was lower among cases (P<0.005) indicating a higher association with Bipolar Spectrum Disorders and MS. Limitations: MS diagnosis was differently collected in cases and controls. Even if this might have produced false negatives in controls, it would have reinforced the null hypothesis of no increased risk for MD in MS; therefore, it does not invalidate the results of the study. Conclusions: This study was the first to show an association between BD and MS using standardized diagnostic tools and a case–control design. The results suggest a risk of under-diagnosis of BD (particularly type II) in MS and caution in prescribing ADs to people with depressive episodes in MS without prior excluding BD. The association between auto-immune degenerative diseases (like MS) and BD may be an interesting field for the study of the pathogenic hypothesis. [Copyright &y& Elsevier]