AIMS: Malignant peripheral nerve sheath tumour (MPNST) is an unusual sarcoma of the heart and should be differentiated from other spindle cell sarcomas. METHODS AND RESULTS: We combined morphological, immunohistochemical and cytogenetic techniques in the differential diagnosis, particularly from monophasic synovial sarcoma. The tumour consisted of dense fascicles, alternating with hypocellular, myxoid zones. There was a marked herniation of tumour cells into the vascular lumen. Immunohistochemically, the tumour cells expressed vimentin and focally S100 protein. There was no expression of cytokeratin or epithelial membrane antigen (EMA). Although we found a complex karyotype, the finding of involvement of 17q11. the loss of chromosome 22, and the absence of a t(X:18)(p11.2:q11.2), which characterizes synovial sarcoma allowed us to the final diagnosis of malignant peripheral nerve sheath tumour. CONCLUSION: MPNST of the heart can be diagnosed by combining morphological and immunohistochemical data. Cytogenetics can be useful in reaching a correct diagnosis, also by helping to rule out monophasic synovial sarcoma.