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Purpose: To determine factors associated with early functional decline during first-line chemotherapy in older patients., Patients and Methods: Patients age ≥ 70 years receiving first-line chemotherapy for cancer were prospectively considered for inclusion across 12 centers in France. Functional decline was defined as a decrease of ≥ 0.5 points on the Activities of Daily Living (ADL) scale between the beginning of chemotherapy and the second cycle. Factors associated with functional decline were sought from pretreatment abbreviated comprehensive geriatric assessment, including ADL, Instrumental ADL (IADL), Mini-Nutritional Assessment (MNA), Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS15), and Timed Get Up and Go (GUG) test, and from comorbidities (Cumulative Illness Rating Scale-Geriatrics), MAX2 index, and baseline biologic and clinical information., Results: Of 364 included patients, 50 experienced functional decline (16.7%; median, 0.5 points). Abnormal preadmission performance status, IADL, GDS15, MMSE, GUG, and MNA were associated with increased likelihood of functional decline (univariate analysis). In the multivariate model adjusted for baseline ADL and MAX2 index, high baseline GDS (odds ratio [OR], 2.16; 95% CI, 1.09 to 4.30; P = .03) and low IADL scores (OR, 2.87; 95% CI, 1.06 to 7.79; P = .04) were independently associated with increased risk of functional decline., Conclusion: Our results outline associations between baseline depression, instrumental dependencies, and early functional decline during chemotherapy for older patients. ADL should be sequentially evaluated early during treatment. Baseline evaluation of GDS15 and IADL may be proposed to anticipate this event.