This prospective cohort study aimed to compare the predictive accuracy of outcome (survival/death) among trauma patients using various prognostic scores. Over 3 months, 240 trauma patients in a tertiary care hospital were assessed for demographic details, trauma characteristics, vital signs, Glasgow coma scale, arterial blood gas values, and lab markers. Injury severity score (ISS), revised trauma score (RTS), trauma and injury severity score (TRISS), and acute physiology and chronic health evaluation II (APACHE II) were applied at admission, 24 hours, and 48 hours post-admission. Road traffic accidents (55.83%) were the primary cause of trauma, followed by falls (33.75%) and violence (10.41%). The all-cause mortality rate was 23.33%, with 34.16% requiring ICU admission. Head injuries (65.83%) were both the most frequent injury site and cause of mortality. Analysis indicated that APACHE II outperformed other scores in predicting outcomes, with ISS following closely. The study concludes that trauma severity correlates with ICU admission and mortality, emphasizing APACHE II as a superior predictor, particularly for traumatic brain injuries leading to ICU admission and mortality. This study contributes to the existing body of knowledge by addressing the gap in comparing prognostic abilities among scoring systems for trauma patients. The unexpected superiority of APACHE II suggests its potential as a valuable tool in predicting outcomes in this specific patient population. Gupta J, Kshirsagar S, Naik S, Pande A. Comparative Evaluation of Mortality Predictors in Trauma Patients: A Prospective Single-center Observational Study Assessing Injury Severity Score Revised Trauma Score Trauma and Injury Severity Score and Acute Physiology and Chronic Health Evaluation II Scores. Indian J Crit Care Med 2024;28(5):475-482.