Background: Older patients have increased risk of toxicity from chemotherapy. The purpose of this study was to analyse predictive factors for developing grade 3-5 toxicity in older patients treated with chemotherapy. Methods: This prospective multicenter study included 500 cancer patients ≥ 70 years between Feb 2014 and Jun 2018. A prechemotherapy assessment including sociodemographics, tumor/treatment variables, laboratory test results, and geriatric assessment variables (function, comorbidity, cognition, psychological state, social activity/support, and nutritional status) was performed. Logistic regression was used to examine the association between these factors and the development of grade 3-5 toxicity. Results: Mean age of the patients was 77 years (70-92), ECOG PS 0/1/2: 25%/63%/12%. 223 (45%) had a primary dose reduction.167 (33%) patients developed grade 3-5 toxicity (28% grade 3, 5% grade 4, 1% grade 5). Univariate analysis found a higher risk of grade 3-5 toxicity in patients with creatinine clearance ≤ 60 mL/min, IADL ≤7, VES13 ≥ 6, and the administration of standard chemotherapy doses. In multivariable analysis, only the chemotherapy dose (odds ratio [OR] 1.179; 95% confidence interval [CI] 1.215–2.655) and creatinine clearance (odds ratio [OR] 0.989; 95% confidence interval [CI] 0.981–0.997) were independently associated with toxicity. Conclusions: Renal function and chemotherapy dose were significant predictors of grade 3-5 toxicity among older patients treated with chemotherapy.