We report a case of diffuse and extreme cytoplasmic vacuolization of tumour cells in a rectal adenocarcinoma after neoadjuvant treatment. A 64-year-old man with a moderately differentiated rectal adenocarcinoma, diagnosed by endoscopic rectal biopsy, underwent surgical treatment after chemoradiotherapy. Residual tumour mass was represented by foci of neoplastic cells with the morphological features of conventional type adenocarcinoma, and surprisingly, by numerous areas consisting of several giant vacuoles, variable in size, merging to form multilocular spaces separated by a rim of cell membrane with a "plant-like" appearance. Cytoplasmic vacuolization may represent a distinct form of cell death, and pathologists should carefully consider this unusual and potentially alarming morphological change among the chemoradiotherapy-induced effects on tumour mass.