We review the literature on management of psychosis and agitation in medical-surgical patients who have or are at risk for prolonged QT interval, a risk factor for torsade de pointes (TdP), and we describe our protocols for treating these patients. We searched PubMed and PsycInfo for relevant studies and found few papers describing options for treating psychosis and agitation in these patients. Prolonged QTc interval has been more often associated with low-potency phenothiazines such as thioridazine; however, it may occur with high potency typical antipsychotics such as fluphenazine and haloperidol as well as with atypical antipsychotics such as quetiapine, risperidone, olanzapine, iloperidone, and particularly ziprasidone. Antipsychotics for which no association with prolonged QTc interval has been shown include lurasidone, clozapine, and aripiprazole. For patients who have risk factors for prolonged QTc interval but whose electrocardiograms do not show this, reasonable first choices include oral or intramuscular olanzapine or aripiprazole, followed by risperidone and quetiapine or oral or intramuscular haloperidol. For those who have prolonged QTc but that measures less than 500 ms, we limit the use of antipsychotics to aripiprazole, olanzapine, risperidone, or quetiapine. Finally, for patients who have a QTc of 500 ms or greater, we rely on aripiprazole, valproate, trazodone, and benzodiazepines.