Cancer cells frequently fail to respond to chemotherapy due to acquisition of chemoresistance. Tumour cells are prone to die by necrosis when they are metabolically stressed by hypoxic and glucose depletion (OGD) due to insufficient vascularization, a common feature of solid tumours. Tumour necrosis indicates poor prognosis and emergence of drug resistance in cancer patients; however, its molecular mechanism remains unclear. In this study, we used multicellular tumour spheroids (MTS) as an in vitro tumour model to investigate the molecular mechanisms underlying necrosis-linked drug resistance. MCF-7 cells formed tight and spherical shape of spheroids and started to form the necrotic core at 8 days of culture. We found that docetaxel (DOC)-induced apoptosis was gradually reduced during MCF-7 spheroid culture compared to that in monolayers and that more prominent resistance to DOC was observed when spheroids containing the necrotic core were treated. ERK1/2 and Akt appeared to be activated in MCF-7 spheroids with necrotic core, but not in 2D culture cells and in spheroids without necrotic core. DOC resistance in spheroids was reversed by inhibition of ERK1/2, but not of Akt, suggesting an important role for ERK1/2 in the DOC resistance in MCF-7 spheroids. These results provide new insight into the possible relation between necrosis-linked ERK1/2 activation and acquisition of multicellular resistance.