Background: A comprehensive geriatric assessment (CGA) systematically appraises the somatic, psychosocial and functional health status of elderly patients. If CGA can predict toxicity of chemotherapy in elderly cancer patients, this assessment could be useful in deciding on optimal treatment. In this analysis, we evaluated the association between frailty on CGA or Groningen Frailty Index (GFI), and grade 3/4 toxicity in metastatic breast cancer (MBC) patients treated with first-line chemotherapy. Methods: In the OMEGA study, MBC patients (≥ 65 years) were randomized between PEGdoxo 45mg/m²every 4 weeks or capecitabine 2000 mg/m² on days 1-14 every 3 weeks. Baseline geriatric assessment included functional status (ECOG performance status (PS), IADL), cognition (MMSE), mood (GDS), comorbidity (Charlson), polypharmacy and undernutrition (BMI) and GFI. Frailty on CGA was defined as one or more of the following: IADL≤13, MMSE ≤23, GDS ≥5, BMI ≤20, ≥5 medications or Charlson ≥2. GFI score for frailty was ≥4. Results: In total, 78 patients were randomized (PEGdoxo 38, capecitabine 40), median age 75 years (range 65-86). ECOG PS was 0-1 in 78% of patients and 2-3 in 22%. So far, 72 patients were evaluable for toxicity and baseline CGA. Overall, 50 patients (70%) were frail on CGA, and 40 (55%) according to GFI. Grade 3/4 toxicity related to chemotherapy was reported in 30 patients (42%) and 50% of CGA-frail patients experienced grade 3/4 toxicity, compared to 20% of CGA-fit patients (p=0.02). Grade 3/4 toxicity was experienced by 44% of GFI-frail patients, compared to 38% of GFI-fit patients (p=0.39). After correcting for type of chemotherapy and age, toxicity was associated with CGA-frailty (odds ratio (OR) 4.00, 95% confidence interval (CI) 1.77-13.59, p=0.03) while GFI-frailty was not associated with toxicity (OR 1.11, 95% CI 0.85-1.46, p=0.43). Conclusions: In this randomized study on first-line single-agent chemotherapy in elderly MBC patients, baseline CGA demonstrated a good predictive value for grade 3/4 toxicity of chemotherapy but GFI did not.