The use of antipsychotic combination has been increasing during the last decade. This study aimed to compare the efficacy and safety of low-dose amisulpride plus low-dose sulpiride with full-dose amisulpride in the treatment of acute schizophrenia. In this 6-week, double-blind, fixed-dose study, patients were randomized to antipsychotic combination (400 mg/day amisulpride plus 800 mg/day sulpiride, N=46) or monotherapy (800 mg/day amisulpride, N=46) groups. Efficacy measurements included the Positive and Negative Syndrome Scale (PANSS) and subscales, and other scales. Safety and quality of life were also assessed. Response was defined as a 30% reduction in the PANSS total score. Both groups were similar in terms of the following: (a) clinical characteristics at baseline, (b) response rates, and (c) score changes in all psychopathology measures, quality of life, and all side-effect scales after 6 weeks of treatment. There were also no significant between-group differences in changes in other safety measurement. However, the combination strategy did reduce treatment costs. The current study suggests that an antipsychotic combination of low-dose antipsychotics is as efficacious and safe as, but cheaper than, optimal-dose monotherapy in the treatment of schizophrenia.