Background: Considerable inter-individual variability in oxaliplatin toxicity exists in older adults with GI cancers. Low lean body mass (LBM), commonly known as sarcopenia, influences toxicity and is not incorporated in standard body surface area-based dosing, which may affect oxaliplatin PK and tolerability, but has not been examined systematically. Methods: We examined oxaliplatin PK in 26 older adults (103 concentrations) with GI cancers (NCT03998202). Using the transverse section at L3, skeletal muscle area (SMA) and total adipose tissue (TAT) were quantified (Slice-O-Matic software) and LBM was calculated (LBM = 0.30 × SMA + 6.06). Noncompartmental methods (WinNonlin 7.0) were used for PK estimates and a one compartment population PK model (PopPK) was developed. Covariates included age, sex, LBM, TAT, weight, BMI, creatinine clearance, BSA, serum albumin, and body composition phenotypes (i.e. low LBM-high TAT, etc.). Results: Median age was 68yrs, 69% male, 88% white, and mostly colorectal (62%) and pancreatic (27%) cancers. There was wide variability in oxaliplatin volume of distribution (Vd: 12.5-259L), peak concentrations (Cmax: 404-3642ng/mL), and clearance (CL: 26.7-270L/hr). Participants with lower LBM had lower Vd (r = 0.51, p< 0.01); those with higher TAT had higher Cmax (r = 0.53, p< 0.01). Higher albumin was associated with lower Cmax (r = -0.49, p= 0.01) and higher CL (r = 0.47, p= 0.01). The phenotype of low LBM + high TAT had the lowest Vd (Relative Risk [RR] 0.32, p= 0.01), lowest CL (RR 0.39, p< 0.01), and highest Cmax (RR 3.3, 95% CI 1.7-6.5, p< 0.01). Eleven patients (44%) had grade 3-5 chemotoxicity. Vd (r = -0.46, p= 0.02) and Cmax (r = 0.44, p= 0.03) were associated with grade 3-5 chemotoxicity. The phenotype of low LBM + high TAT was associated with a 45% higher risk of grade 3-5 chemotoxicity (RR = 1.45, 95% CI 1.1-2.1, p= 0.04), while BSA was not (r = -0.04, p= 0.9). In the popPK model, body composition was associated with PK (TAT with Vd [p = 0.006] and CL [p < 0.001]), as was albumin (Vd p = 0.004; CL p = 0.002), while BSA was not (Vd p = 0.08; CL p = 0.2). Compared to BSA, an additional 11-17% in oxaliplatin PK variability was explained by LBM (11%), TAT (14%), and albumin (17%). Conclusions: Relationships between body composition, oxaliplatin PK, and severe chemotoxicity suggest the need for novel dosing strategies that incorporate body composition to reduce chemotoxicity and improve outcomes. Clinical trial information: NCT03998202