3156 Background: Phase I clinical trials (CT) report adverse events (AEs) using the Common Terminology Criteria for AEs (CTCAE) version 5.0. If multiple qualitatively AEs are recorded in a trial, this results into manifold AE counts. Total toxicity burden (TTB) is defined for each patient as the sum of the highest grade of each AE divided by the number of AEs recorded [Thall, 2003]. We computed the TTBs for five groups of drugs studied in phase I trials. Methods: Pts treated from 2016 to 2022 in the phase I CT unit at MD Anderson Cancer Center were included. Clinical baseline prognostic factors [ECOG, age, Carlson comorbidity index (CCI)] were included and analyzed. AEs according to the CTCAE v5.0 were collected and simplified into 21 categories per trial and patient. Treatments were divided into: Cytotoxic agents (Chemo), Targeted Therapy (TT), Immune checkpoint inhibitors (ICI), Chimeric antigen receptor T cells (CART), or Cytokines (CYT). Using regimen-related AEs for evaluable patients, mean (SD) TTB for each treatment group was computed using each patent’s worst grade as the severity weight for each type of AE. Results: A total of 1322 evaluable pts from an initial sample of 2,350 were collected. Median age was 61 years (range, 19-92), 75.6% ECOG PS 1, median CCI was 8, and all pts were treated in a phase I/II CT. A total of 1782 AEs were treatment related and 3071 AEs were not treatment related. 715 evaluable pts (54.1%) had at least one treatment-related AE, and 902 patients (68.2%) had at least one treatment unrelated AE. A total of 265 (20.0%) grade 1 (G1) treatment-related AEs, 231 (17.5%) G2, 184 (13.9%) % G3, and 29 (2.2%) G4, and one G5 was reported. The most frequent G≥3 AEs overall were Neutropenia (N=54), Anemia (N=52), and low platelets (N=35). The most frequent G≥3 AEs per treatment group were Neutropenia (10%), Anemia (15%), and increased AST/ALT (13%) in group Chemo, Neutropenia (8%), Low platelets (9%), and Anemia (9%) in group TT, Increased AST/ALT (10%), Anemia (5%), and Pain (5%) in group ICI, Neutropenia (10%), Anemia (10%), and Low platelets (5%) in group CART, and Nausea/Vomit (3%), Pneumonitis (1%), and Infection (1%) in group CYT. Mean TTBs for the five treatment groups were 2.7 (SD=3.3) for Chemo, 2.9 (SD=3.6) for TT, 1.7 (SD=1.9) for IO, 5.9 (SD=5.1) for CART, and 0.8 (SD=1.8) for CYT. Corresponding G≥3 treatment-related AE rates were 21.7%, 21.0%, 12.2%, 52.4%, and 6.4% in the five treatment groups. It appears that CART is the most toxic treatment group based on TTBs and conventional analysis based on G>3. These results suggest that propensity score-based comparisons of mean TTB to correct for selection bias using prognostic variables are warranted. Conclusions: TTB is a useful tool to quantify the mean severity of qualitatively different types of adverse events experienced by patients in a clinical trial, and mean TTB may be compared between treatment groups.