Solid pseudopapillary neoplasm of the pancreas (SPN) is a rare low-grade malignant neoplasm. To our knowledge, SPN with prominent atypical multinucleated giant tumour cells (MNGTCs) has not yet been reported.We identified four cases of SPN with prominent atypical MNGTCs in a cohort of 62 cases of SPN (6.5%). The MNGTCs contained multiple enlarged, hyperchromatic, irregular nuclei with ample eosinophilic cytoplasm, typically present in the solid area of the tumour. The MNGTCs had an immunohistochemical profile typical of the conventional SPN and were positive for vimentin, β-catenin, CD10 and progesterone receptor, but negative for pan-cytokeratin, chromogranin, synaptophysin, trypsin, Ki-67 and CD68 in all four cases. Patients of SPN with prominent MNGTCs were older than those with conventional SPN (P = 0.01); tumours were discovered incidentally by imaging studies for an unrelated disease in all four cases, and with a female to male ratio of 1:1. The proliferation index (Ki-67) was <1% in all four cases. None of the three patients for whom information was available developed recurrence during follow-up of 2.7, 3.8 and 5.0 years.The presence of MNGTCs in SPN most probably represents degenerative change of the tumour cells and does not seem to affect the prognosis.