Our objective was to determine the effectiveness of lamotrigine in treating painful polyneuropathy. Medications active at neuronal sodium channels have been reported to be effective in treating painful polyneuropathy. Twenty-one adults with painful polyneuropathy were randomly assigned 2:1 to receive lamotrigine or placebo. Patients were slowly titrated to 200 mg/d lamotrigine or placebo. After 2 weeks, those without adequate pain control were titrated to a maximum of 500 mg/d. Patients completed the Short Form McGill Pain Questionnaire/Visual Analog Scale (VAS) at each of seven office visits and completed pain and sleep disturbance diaries daily. Mean VAS and pain and sleep diary scores were compared using Student's one-tailed t test. Lamotrigine-treated patients had significantly lower mean VAS scores than placebo-treated patients at visits 6 (p ฯญ 0.03) and 7 (p ฯญ 0.04) and a significant dose-response relationship was seen above 300 mg/d (p ฯญ 0.03). Patients tolerated the study medication well, with 1 dropout for side effects and 6 for other reasons (increasing pain, 2; medicine for unrelated condition, 2; noncompliance with visit schedule, 1; unrelated condition, 1). The most common adverse event was upper respiratory infection (2 in each group), with no rash or somnolence reported. Lamotrigine appears to be an effective and well-tolerated treatment for painful polyneuropathy. Larger trials to confirm this finding are warranted.