In a preliminary investigation, zonisamide, an antiepileptic drug, administered at up to 600 mg/d, led to 6% weight loss (vs 1% for placebo) over 16 weeks in obese adults. This randomized controlled trial examined the weight loss efficacy of 2 doses of zonisamide (200 mg and 400 mg) vs placebo in 225 obese adults over 1 year. Change in body weight was −4.0 kg (95% CI, −5.8 kg to −2.3 kg) for placebo; −4.4 kg (95% CI, −6.1 to −2.6) for zonisamide, 200 mg; and −7.3 kg (95% CI, −9.0 to −5.6) for zonisamide, 400 mg. A weight loss of 10% or greater was achieved in 8% of patients assigned to placebo; 22% of patients assigned to zonisamide, 200 mg; and 32% of patients assigned to zonisamide, 400 mg. Gastrointestinal, nervous system, and psychiatric adverse events occurred at a higher incidence with zonisamide than with placebo. The authors conclude that zonisamide, 400 mg, moderately enhanced weight loss achieved with diet and lifestyle counseling but had a high incidence of adverse events.