Delirium is a potentially life-threatening syndrome that is particularly common in elderly hospitalized patients, especially those with preexisting neurologic disorders. Nonpharmacological tactics can reduce the incidence and severity of delirium in acute care settings and antipsychotic drugs are widely used to treat established delirium. More effective preventive strategies could notably impact morbidity, mortality, and health care costs. To determine whether antipsychotic drug prophylaxis reduces the incidence and severity of postoperative delirium in at-risk elderly patients. We addressed the objective through development of a structured critically appraised topic that included a clinical scenario, structured question, search strategy, critical appraisal, results, evidence summary, commentary, and conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of cognitive disorders. One randomized controlled trial addressed the question. In at-risk patients aged >70 years, oral haloperidol 0.5 mg TID, administered from up to 72 hours preoperatively until the third postoperative day, did not alter the incidence of postoperative delirium (15.1%) compared with placebo (16.5%; relative risk 0.91; 95% confidence interval 0.59-1.44). However, the study was underpowered for this primary outcome, possibly because both groups received nonpharmacological delirium prevention strategies. Haloperidol significantly reduced delirium severity ratings, delirium duration (from a mean of 11.8 to 5.4 days), and length of hospital stay in affected participants (from 22.6 to 17.1 day). Adjunctive low-dose haloperidol prophylaxis reduces delirium severity, duration, and subsequent hospitalization length in elderly at-risk patients. Further study is needed to determine the optimal pharmacological approach, combination with nonpharmacological strategies, and generalizability to other settings.