BACKGROUND : Cognitive deficits are a core feature of bipolar disorder (BD), and persist during the euthymic phase. White matter (WM) microstructural abnormalities are widely considered a structural marker of BD. Features of illness chronicity, such as illness duration and number of mood episodes, have been associated with worsening of both clinical profile and brain structural alterations. This study examined the role of WM integrity as a possible mediator between illness duration and cognitive performances in a sample of BD patients. METHODS : We assessed 88 inpatients affected by a depressive episode in course of type I BD for verbal memory, visual memory, working memory, visuospatial constructional abilities, psychomotor coordination, executive functions, processing speed, and verbal fluency. White matter integrity was evaluated through FA measurements derived using the Enhancing Neuro Imaging Genetics Through Meta-Analysis (ENIGMA)-DTI protocol. RESULTS : The effect of illness duration on processing speed, verbal memory, and visual memory was mediated by the FA values of bilateral anterior corona radiata, bilateral corona radiata, genu of corpus callosum, and fornix, adjusting for age, sex, education and lithium treatment (p < 0.05). CONCLUSIONS : Potential interaction factors were not examined in this study. CONCLUSIONS : This is the first study to show the role of WM integrity as a mediator of the negative effect of illness duration on cognitive performances. Our data provide new insight into the neuroprogressive hypothesis of BD.