Background: Treatment decisions in older adults with cancer are confounded by limited evidence due to their under-representation in clinical trials and as associations between geriatric assessment findings, body composition measures, treatment-related toxicity, and treatment effectiveness have yet to be fully elucidated. We investigated the relationship between geriatric assessment results, skeletal muscle measures, and treatment-related toxicity in older adults with cancer. Methods: This prospective single-center cohort study included patients with cancer > 65 years of age with advanced lung, breast, or genitourinary (GU) cancer who received systemic treatment (chemotherapy, biologic therapy, immunotherapy, or combination), and had available CT scans. Patients completed the Comprehensive Geriatric assessment (CGA) and 36-item Carolina Frailty Index (CFI) was calculated to classify them as robust ( < 0.2), pre-frail (0.2-0.35), or frail ( > 0.35). For each patient, skeletal muscle area (SMA) and density (SMD) were analyzed from CT scan L3 lumbar segments using Slice-O-Matic software. SMA and height (m²) were used to calculate skeletal muscle index (SMI). Skeletal muscle gauge (SMG) was created by multiplying SMI x SMD. Sarcopenia was defined as having SMI < 41 cm²/m² for males and < 38 cm²/m² for females. The associations between study variables and the occurrence of at least one adverse event (AE) grade ≥2 were analyzed using the Pearson's chi-squared test. The study was approved by the IRB of Rambam Health Care Campus. All patients signed an informed consent. Results: Overall, 51 patients (recruited between 5/2015 and 1/2020) were included in the final analysis. Median (interquartile [IQR]) age was 72 (68-76) years; 59% were male; 51%, 28%, and 22% had lung, breast, and GU cancer respectively. The most common treatment received was doublet chemotherapy (49%). All patients except 3 (6%) completed the CGA and CFI was calculated; 29%, 26%, and 39% were classified as robust, pre-frail, and frail, respectively. Median (IQR) SMG was 1251 (1104-1497) AU; median (IQR) SMI was 42 (39-48) cm²/m²; 31% were defined as sarcopenic. Overall, 45% of patients experienced at least one AE grade ≥2; 24% experienced at least one AE grade≥3. No statistically significant association was found between treatment-related toxicity and sex, age, tumor type, treatment, or CFI category. Yet, having low SMG (categorically, by tertile) was significantly associated with having at least one AE grade≥2 (p = 0.03) as was being sarcopenic (p = 0.02). Conclusions: Low SMG and sarcopenia are associated with treatment-related toxicity in older patients with cancer. Further research and better understanding of this association could help optimize treatment decisions (e.g., choice of regimen, dosing) and interventions in this population.