Myxofibrosarcoma is one of the most frequent soft tissue tumours in elderly patients, mostly arising in the extremities. Grade I lesions are only locally aggressive whereas grade II and grade III lesions have metastatic potential. The differential diagnosis contains several other (benign) myxoid soft tissue tumours. A number of sarcomas are characterised by specific cytogenetic aberrations, giving not only insight in their biological pathways; they also serve as molecular markers in difficult diagnoses. Cytogenetic data on myxofibrosarcoma are scarce with only few isolated cases described in the literature. No specific chromosomal aberrations have been detected so far. Moreover, molecular pathways in tumorigenesis and progression of myxofibrosarcoma are barely understood. We studied the clinicopathologic data and karyotypes of 32 myxofibrosarcomas using conventional banding and multicolour COmbined Binary RAtio labelling fluorescence in situ hybridisation technique. We included eight grade I, eight grade II and 16 grade III lesions. In all, 22 were primary tumours, nine were local recurrences and one a lymph node metastasis. The myxofibrosarcomas showed equal sex distribution, were mostly located at the extremities with two thirds deep-seated and had an average age of occurrence of 66 years. We found normal karyotypes in eight cases and clonal beside nonclonal aberrations in 22 cases. Complex cytogenetic anomalies were found in all grades. However, no tumour-specific chromosomal abnormalities could be withdrawn. Local recurrences showed increase in grade compared to their primary lesions. Interestingly, these recurrences showed more complex cytogenetic aberrations. Increase in grade seems to parallel increase in cytogenetic aberrations and malignant potential. Since the chromosomal aberrations found were not tumour type specific, they seem to be rather the result of secondary events in tumour progression and tumour genetic instability. Based on these findings, we suggest that tumorigenesis of myxofibrosarcoma is mainly a multistep genetic process, probably ruled by genetic instability caused by targeted checkpoint genes.