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Background: The co-occurrence of bipolar disorder and substance use is frequent. The question whether substance use precedes, induces or follows bipolar disorder is still unresolved. Substance use has been typically represented as a negative prognostic factor for the clinical course of bipolar illness and it has been associated with decreased compliance and treatment resistance. To extend these previous findings we examined the clinical course and outcome of patients with bipolar disorder I or II whose bipolar onset was preceded by substance/alcohol use., Methods: The impact of substance use as a predisposing or precipitating factor of a bipolar episode was evaluated by comparing a group of bipolar subjects whose mood symptomatology onset was preceded by substance/alcohol use (N=145) (SUBP) with a similar sized representative sample of bipolar patients (either substance users/abusers or not using substances) whose first mood episode was unrelated to substance use (N=144) (NSUBP). RESULTS; The analysis of clinical and socio-demographic variables revealed that patients in the SUBP group showed less severe psychopathology, as indicated by fewer total hypomanic and depressive episodes during the course of their illness. Depressive onset was less frequent amongst the SUBP group. SUBP patients, compared to NSUBP, were poorly compliant to treatment., Conclusions: Bipolar disorder preceded by substance misuse may represent a clinically milder subtype of bipolar illness. This subtype would be less "primary" and might be more early targeted by primary prevention with programmes focused on substance misuse.