Background: Serotonin (5-HT):dopamine imbalance may underlie neuroleptic-induced akathisia. Aim: To evaluate the efficacy of the 5-HT2 antagonist, mianserin in neuroleptic-induced akathisia. Methods: Thirty neuroleptic-treated patients with schizophrenia were randomly allocated in a double-blind design to receive either mianserin (15 mg/day) or placebo for five days. Patients were assessed at baseline and on Days 3 and 5 by the Barnes Akathisia Scale (BARS), as well as by other relevant clinical rating scales. Results: Compared with the placebo group, the mianserin-treated patients showed a significant reduction in all four BARS subscales by Day 5, with mean reductions in the BARS global score of 9.9% and 52.2%, respectively (P=0.006). Response to treatment (a reduction of at least two points on the BARS global subscale), was noted in six patients (40%) in the mianserin group and only one patient (9.1%) in the placebo group (P=0.04, log odds ratio 2.23). Conclusions: Mianserin at a low dose may be a promising therapeutic option for patients with acute neuroleptic-induced akathisia. Declaration of interest: This study was supported by a grant from Rafa Pharmaceutical Company, Jerusalem, Israel.