A number of research studies support the weight loss effects of metformin and topiramate for obese people with schizophrenia. However, only a few studies have addressed the sustainability of the body weight reduction after discontinuation of these drugs. Moreover, head-to-head studies are still lacking. The study aims to evaluate and compare the efficacy of metformin and topiramate in weight reduction and weight maintenance after discontinuation of these drugs in obese people with schizophrenia. Twenty-two obese inpatients with schizophrenia were recruited and randomized into the metformin group (n = 11; daily dose, 1000 mg) and the topiramate group (n = 11; daily dose, 100 mg). A head-to-head, fixed-dose, and single-blinded design was used. Ten obese patients with schizophrenia of similar sex as that of the treated group were included as the control group. After a 4-month treatment, the metformin group showed a body weight reduction of 3.8 kg, and the topiramate group showed a reduction of 2.7 kg. However, the reduction could be sustained only in the metformin group at 3 and 9 months after metformin discontinuation. Interestingly, 3 months after treatment discontinuation, leptin levels showed a reduction in both metformin (baseline, 25.3 ± 14.7, week 7: 5.7 ± 3.7 ng/mL) and topiramate (baseline: 28.4 ± 16.1, week 7: 9.2 ± 15.5 ng/mL) groups. The trend of weight changes supports the superiority of metformin at 1000 mg/d over topiramate at 100 mg/d in weight reduction and weight maintenance.