The purpose of the present study was to prospectively examine the association between treatment adherence and common neuropsychiatric symptoms in multiple sclerosis (MS). Patients underwent a thorough psychiatric and neuropsychological evaluation at the outset of the study. Patient adherence to disease modifying therapies was then tracked for 8 weeks using self-report, a medication diary, and an electronic monitoring device that recorded needle disposals. Results indicated that MS patients with current mood or anxiety disorders were almost five times as likely as MS patients with no psychiatric diagnosis to exhibit problems adhering to their disease modifying therapies. Poor adherence was also associated with memory difficulties, anxiety, depression, neuroticism, and low conscientiousness. Findings highlight the importance of conducting a thorough psychiatric and neuropsychological evaluation when clinicians suspect poor adherence to disease modifying therapies. Pharmacological or psychotherapeutic treatment of mood/anxiety disorders, use of scheduled reminders, and/or increased organization and structure may lead to improved treatment adherence in MS.