Cyamemazine is an anxiolytic antipsychotic, which reduces ethanol withdrawal symptoms. Here, we investigated if cyamemazine can be also effective as substitute drug to facilitate benzodiazepine withdrawal. A total of 168 patients treated with benzodiazepines for at least 3 months and with a <18 score in the Hamilton Anxiety Rating Scale (HARS) were included in the study. Previous benzodiazepine treatment was withdrawn, and patients were randomized to a 4-week treatment with cyamemazine (25-50 mg q.d.) or bromazepam (3-6 mg q.d.), followed by 2 weeks of placebo. The primary efficacy variable was the maximal anxiety rebound as measured with the HARS during the 42 days of treatment. No statistically significant differences between treatment groups were found for the extent or incidence of rebound anxiety. Considering all dropout patients as withdrawal failures, after 6 months of follow-up, 56/84 patients in the cyamemazine group (66.7%) and 55/84 patients in the bromazepam group (65.5%) were successfully withdrawn. 28 patients in the cyamemazine group and 18 in the bromazepam group had an adverse event, including anxiety, insomnia, dry mouth and somnolence. No extra-pyramidal symptoms were reported. In conclusion, cyamemazine was comparable to bromazepam in ensuring successful benzodiazepine withdrawal and in controlling the acute benzodiazepine withdrawal syndrome. Cyamemazine may be useful to facilitate benzodiazepine withdrawal in those patients where bromazepam substitution is not appropriate.