Objective To demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the intensive care unit (ICU) and to test the hypothesis that antipsychotics would improve days alive without delirium or coma. Design Randomized, double-blind, placebo-controlled trial. Setting Six tertiary care medical centers in the United States. Patients 101 mechanically ventilated medical and surgical ICU patients. Intervention Patients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hours for up to 14 days. Frequency of administration was adjusted twice daily according to delirium status, level of sedation, and side effects. Measurements and Main Outcomes The primary end point was the number of days patients were alive without delirium or coma. During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [IQR], 14.0 [6.0–18.0] days) as did patients in the ziprasidone (15.0 [9.1–18.0] days) and placebo groups (12.5 [1.2–17.2] days) (p = 0.66). No differences were found in secondary clinical outcomes, including ventilator-free days (p = 0.25), hospital length of stay (p = 0.68), and mortality (p = 0.81). Ten (29%) patients in the haloperidol group reported symptoms consistent with akathisia, compared with 6 (20%) patients in the ziprasidone group and 7 (19%) patients in the placebo group (p = 0.60), and a global measure of extrapyramidal symptoms was similar between treatment groups (p = 0.46). Conclusions A randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated ICU patients is feasible. Treatment with antipsychotics in this limited pilot trial did not improve the number of days alive without delirium or coma nor did it increase adverse outcomes. Thus, a large trial is needed to determine whether use of antipsychotics for ICU delirium is appropriate.