Objective Cyamemazine is an original phenothiazine derivative which showed similar efficacy and tolerability to lorazepam during ethanol withdrawal in mice. This study investigated cyamemazine for its efficacy and tolerability in alcoholdependent patients electing an alcohol withdrawal procedure, in comparison with diazepam. Method A multicenter, randomized, double-blind study in 89 alcohol-dependent patients (CIWA-Ar score between 10 and 30), electing an alcohol withdrawal procedure, was used to find effective doses of cyamemazine and to compare it with diazepam for efficacy and tolerability. On day 1 (D 1 ), cyamemazine or diazepam (50 mg and 10 mg capsule, respectively) were administered at hourly intervals to reduce CIWA-Ar ¼ 5, up to a maximum of eight administrations. Starting from D 2 , the compounds were given twice a day in progressively decreasing doses during a maximum period of 13 days (D end ). Results At h 8 (8 h after the first treatment of D 1 ), therapeutic success (CIWA-Ar score 5) was achieved in 32 out of 43 ITT patients treated with cyamemazine (74.4%), a value very similar to that of diazepam (32/44; 72.7%). Most such patients (29/32) were controlled with 2-6 capsules of cyamemazine (100-300 mg). In the PP population, cyamemazine (n ¼ 28) was significantly non-inferior to diazepam (n ¼ 33), with a threshold of 10% for non-inferiority bound and 2.5% for one-sided type I error rate. Such therapeutic similarity was confirmed by the analysis of other efficacy criteria. Safety analysis did not show substantial differences between the two treatments. Conclusions Cyamemazine showed similar efficacy and tolerability to diazepam for the treatment of alcohol withdrawal symptoms at therapeutic doses in the range 100-300 mg.