The goal of the present study was to investigate the involvement of the upper urinary tract (UUT) in patients with multiple sclerosis and its relationship with other neurological and urological features of the disease. One hundred sixteen patients underwent complete neurological and urological assessments, urodynamic investigation, and morphofunctional study of the urinary tract by ultrasonography, voiding cistourethrography, and/or intravenous excretory pyelography. The most remarkable relationships were observed among disease duration, pyramidal system score, amplitude of uninhibited detrusor contractions and the presence of bladder morphological abnormalities (P = 0.03, 0.0008, and 0.018, respectively) and the relationship between pyramidal system score or the presence of bladder pathology and UUT abnormalities (P = 0.03 and 0.0006, respectively). A significant relationship was found between the maximum amplitude of uninhibited contractions and UUT involvement (P = 0.002). No other significant relationship was observed between UUT involvement and any other urodynamic or urological features of the disease (type of progression and progression rate, Expanded Disability Status Scale, and other functional system scores). The relationship among disease duration, high vesical pressures, and the lack of reliable clinical indices of risk to the UUT stress the importance for patients with multiple sclerosis to adhere to a strict follow-up program with urodynamic assessment and urinary tract imaging and to maintain detrusor relaxation with anticholinergic medications.