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Introduction: Agitation and delirium are estimated to occur in 80% of critically ill patients admitted to the intensive care unit (ICU). Critically ill patients experiencing agitation and delirium may benefit from short term use of atypical antipsychotics. There is a paucity of data comparing these agents; therefore, there is no gold standard treatment. This study aims to compare and evaluate the efficacy of olanzapine and quetiapine in the treatment of agitation and delirium in the ICU. Methods: This retrospective cohort analysis evaluated the primary outcome of delirium duration while on either olanzapine or quetiapine, validated via CAM ICU scores. The population included patients admitted to a medical or surgical ICU at a tertiary medical center. Secondary outcomes included ICU length of stay, antipsychotic therapy duration, and incidence of antipsychotic discontinuation prior to ICU discharge. Patient and hospital course characteristics were described using medians and interquartile ranges (IQR) for continuous variables and percentages for categorical variables. Results: Data from 200 patients was analyzed, including 87 who received olanzapine and 113 who received quetiapine. The average duration of delirium was five days in both groups (5 [2-7] vs. 5 [3-7], p=0.447). The duration of antipsychotic therapy was also similar, at a median of nine days for olanzapine and eight days for quetiapine (9 [5-19] vs. 8 [5-15], p=0.510). ICU length of stay was shorter for patients receiving olanzapine compared to quetiapine (11 [7-18] vs. 14 [9-27], p=0.043). Although a greater number of patients receiving quetiapine were mechanically ventilated at baseline than those receiving olanzapine (64% vs. 44%, p=0.003), there was no statistically significant difference in overall duration of mechanical ventilation (8 [8-18] vs. 11 [8-20], p=0.068). Antipsychotic therapy was continued upon ICU discharge in 40 patients receiving olanzapine and 41 patients receiving quetiapine (46% vs. 26%, p=0.166). Conclusions: While olanzapine and quetiapine may have different effects on medication use patterns, particularly among those on mechanical ventilation, both antipsychotics appear similarly effective and well-tolerated in managing ICU-related agitation and delirium.