Two patients were treated for intractable pain secondary to work-related injuries. The first patient, a 48-year-old female, presented in November 1993 with neck pain due to soft tissue myofascial pain, arm pain due to a brachial plexus stretch injury, and clinical depression. Pain management was complicated by a long history of atypical depression. The second patient, a 45-year-old male, was diagnosed in February 1996 with pain due to brachial plexopathy, and subsequently developed depression. Despite administration of multiple antiepileptic drugs (AEDs), antidepressants, and analgesics (including opioids), the pain remained uncontrolled in both patients. Zonisamide (Zonegran®, Elan Pharmaceuticals), a synthetic sulfonamide derivative, is approved as adjunctive therapy for the treatment of patients with partial seizures. Zonisamide (100 mg daily) was administered to each of the patients described because of its potential efficacy in patients with intractable pain, the ability to dose once daily due to a long half-life (t12=63 hr) which may improve compliance, and the relatively low number of drug-drug interactions. Both patients achieved sustained substantial improvement in pain control, including taking fewer medications for pain and improved activity levels. Patient 1 experienced a sustained improvement in mood, psychiatric condition, and depression, and increased function in daily activities. Patient 2 experienced improved ability to resume light carpentry and other light repair work. Additionally, his work tolerance increased from 1 to 4 hrs/day. Zonisamide may be a good choice for patients with intractable neuropathic pain, particularly those who are receiving multiple medications for comorbidities. Zonisamide is thought to have multiple mechanisms of action, which may benefit more patient types than AEDs with a single mechanism of action. The possible mechanisms of action will be discussed.