Purpose: Elderly patients form a heterogeneous population. Evaluation of geriatric factors may help evaluate a patient's health status to better adapt treatment. Patients and Methods: Elderly patients with previously untreated metastatic colorectal cancer (mCRC) were randomly assigned to receive fluorouracil (FU) -based chemotherapy either alone or in combination with irinotecan (IRI) in the Fédération Francophone de Cancérologie Digestive (FFCD) 2001-02 study. Sites participating in the geriatric substudy completed geriatric screening tools to perform prognostic factor analyses for treatment safety during the first 4 months after treatment initiation. Results:The geriatric score was calculated in 123 patients (44%). Median age was 80 years (range, 75 to 91 years). The Charlson comorbidity index was ≤ 1 in 75%, Mini-Mental State Examination (MMSE) score was ≤ 27/30 in 31%, and Instrumental Activities of Daily Living (IADL) showed impairment in 34% of the patients. Seventy-one patients (58%) had grade 3 to 4 toxicity, 41 (33%) had a dose-intensity reduction of more than 33%, and 54 (44%) had at least one unexpected hospitalization during the first 4 months after starting treatment. In multivariate analysis, significant predictive factors for grade 3-4 toxicity were IRI arm (odds ratio [OR], 5.03), MMSE ≤ 27/30 (OR, 3.84), and impaired IADL (OR, 4.67); for dose-intensity reduction of > 33%, the significant predictive factors were alkaline phosphates > 2 × upper limit of normal (OR, 4.16) and IRI arm (OR, 6.85); and for unexpected hospitalization, significant predictive factors were MMSE ≤ 27/30 (OR, 4.56) and Geriatric Depression Scale ≤ 2 (OR, 5.52). Conclusion: Geriatric factors (MMSE and IADL) are predictive of severe toxicity or unexpected hospitalization (MMSE) in a randomized prospective phase III study in mCRC. These results suggest that cognitive function and autonomy impairment should be taken into account when choosing a regimen for chemotherapy.