Persons with multiple sclerosis (PwMS) are at an elevated risk of depression. Decreased Conscientiousness may affect patient outcomes in PwMS. Low Conscientiousness has a strong correlation with depression. Previous work has also reported that white matter (WM) tract disruption in frontal-parietal networks explains reduced Conscientiousness in PwMS.We hypothesized that Conscientiousness-associated WM tract disruption predicts new-onset depression over 5 years in PwMS and evaluated this by assessing the predictive power of mean Conscientiousness associated frontal-parietal network (CFPN) disruption in PwMS for clinically diagnosed depression over 5 years.This longitudinal retrospective analysis included 53 PwMS who were not previously diagnosed as depressed. All participants underwent structural MRI. Medical records were reviewed to evaluate diagnosis of depression for these patients over 5 years. WM tract damage between pairs of gray matter regions in the CFPN was measured using diffusion imaging. The relationship between CFPN disruption and depression was analyzed using logistic regression.Participants with MS had a mean age of 46.0 years (SD = 11.2). 22.6% (n = 12) acquired a diagnosis of clinical depression over the 5-year period. Baseline disruption in the CFPN was a significant predictor (ROC AUC = 61.8%). of new-onset clinical depression, accounting for age, sex, lateral ventricular volume, disease modifying treatment, and lesion volume.Baseline CFPN disruption is associated with progression to clinical depression over 5 years in PwMS. Development of new WM pathology within this network may be a risk factor for depression.