The present study aimed to: (i) provide preliminary data on the effectiveness and tolerability of atypical antipsychotics, amisulpride (AMSP) and quetiapine (QTP) for patients with delirium and (ii) investigate whether the two drugs affect sleep differently and further relation with the recovery time of delirium. Forty patients with delirium were randomly assigned to either AMSP or QTP groups, with a flexible dosing schedule. The Delirium Rating Scale-revised-98 (DRS-R-98) and clinical global impression-severity (CGI-S), total sleep time and quality of sleep were assessed daily. Sixteen subjects in the AMSP group and 15 subjects in the QTP group completed the study. The mean daily dose was 156.4 mg/day and 113 mg/day in the AMSP and QTP groups, respectively. There was no significant difference in the baseline DRS-R-98 and CGI scores. After treatment, DRS-R-98 scores were significantly decreased from the baseline in both treatment groups (P<0.001) without group difference. The mean duration of stabilization were 6.3+/-4.4 days for the AMSP group and 7.4+/-4.1 days for the QTP group without group differences. There was no group difference in the mean quality of sleep score and the mean total sleep time. The duration of stabilization was inversely correlated with the mean sleep quality score and the mean total sleep time (P<0.001). Both atypical antipsychotics were generally well tolerated. The present study shows that both amisulpride and quetiapine may be useful drugs for the treatment of delirium on the basis of effectiveness and relative lack of adverse events. Further systematic controlled studies are required.