The purpose of this study was to investigate the efficacy of cyproheptadine, an antiserotonergic agent, in the treatment of neuroleptic-induced akathisia (NIA), as compared with propranolol, the current gold standard. In a double-blind trial, 30 patients with schizophrenia and NIA received either cyproheptadine 16 mg/day (N = 18) or propranolol 80 mg/day (N = 12) for 4 days, followed by 3 days without any anti-NIA treatment. The Barnes Akahisia Scale, Simpson-Angus Extrapyramidal Effects Rating Scale, and Brief Psychiatric Rating Scale were used to assess the severity of NIA, parkinsonism, and psychosis, respectively. In both groups, the severity of NIA decreased significantly over time (cyproheptadine, -46%; propranolol, -42%), with no significant intergroup difference. The NIA symptoms worsened significantly when cyproheptadine and propranolol were discontinued. We conclude that cyproheptadine 16 mg/day is as effective as propranolol for the treatment of acute NIA. The antiakathisic effect of cyproheptadine may be mostly attributable to its serotonin antagonistic activity.