Clinicians often reduce chemotherapy doses when treating obese patients because of concerns about overdosing. We assessed dose-response according to body-mass index (BMI) and oestrogen receptor (ER) expression of the primary tumour in premenopausal patients with node-positive breast cancer treated with classical CMF (cyclophosphamide, methotrexate, and 5-fluorouracil). Obese patients were significantly more likely to receive a lower chemotherapy dose (<85% of expected dose) for the first course than were those with normal or intermediate BMI (39%vs 16%, p<0.0001). For obese patients and for the total population, reducing the dose of chemotherapy was associated with a significantly worse outcome for the ER-negative cohort (total population hazards ratio 85%vs <85% 0.68 [95% CI 0.54-0.86] for disease free survival; 0.72 [0.56-0.94] for overall survival) but not for the ER-positive cohort (1.16 [0.97-1.40] for disease-free survival; 1.16 [0.94-1.44] for overall survival) [interaction p values=0.0001 for disease-free survival and 0.0019 for overall survival]. Our findings suggest that for women with ER-absent or ER-low tumours, reduction in chemotherapy dose should be avoided.