Background: Obesity is not clearly associated with toxicity of chemotherapy, and ASCO’s guidelines recommend full-weight based dosing. Appropriate consideration of comorbidity is also especially advised in obese patients. However, only limited data exist regarding the combined effects of obesity and comorbidity on toxicity of adjuvant chemotherapy for BC. Methods: We prospectively recruited patients with early BC receiving anthracyclines and/or taxanes-based adjuvant/neoadjuvant chemotherapy between 2012 and 2014 in a single center. Body mass index (BMI) and Charlson comorbidity index (CCI) were calculated before treatment. Acute toxicity of chemotherapy was scored according to NCI-CTCAE criteria. Dose modifications (delays or reductions), treatment discontinuation, toxicity-related hospital admissions and episodes of febrile neutropenia were registered. Comparisons of toxicity between groups were performed with Chi² test. T-test was used for quantitative data. Results: A total of 217consecutive BC patients were included; median age: 50 (25-80); ECOG: 0, 79.2%, and 1, 20.4%; median BMI: 27.1 (14.9-27.2), with 60 obese patients (BMI > 30). Median CCI was 3.2 (0.6-7), with 28.6% showing CCI > 4. Chemotherapy regimens: FEC/AC, 17.1%; FEC/AC-wPaclitaxel, 24.9%; TAC, 34.6%; AC-Docetaxel, 19.8%; TC or wPaclitaxel, 3.7%. Obesity and comorbidity (CCI > 4) were significantly associated neither with grade 3-4 toxicity (hematologic or non-hematologic) nor with hospital admissions or dose modifications. The group of patients (12.5%) with both obesity and CCI > 4 had more frequent dose delays (40.7% vs 21.2%; p = 0.02) and treatment discontinuations (18.5% vs 6%; p = 0.038). Grade 2-3 neurotoxicity (44.4% vs 11.2%; p < 0.001) and thromboembolic events (18.5% vs 4.2%; p = 0.004) were also especially frequent in this group. Conclusions: Although obesity and comorbidity do not have a clear independent impact on BC adjuvant chemotherapy toxicity, a group of women with combined obesity and comorbidity (CCI > 4) show a higher risk of toxicities potentially leading to functional impairment. A higher frequency of chemotherapy delays and interruptions in this group might also compromise its efficacy.