Abstract The question whether radiation-induced thyroid cancer differs by its molecular biology from sporadic disease still remains. Studies on tissue from patients who developed thyroid cancer after the Chernobyl accident have provided a unique opportunity to look for biological consequences of low-dose irradiation by comparing the gene expression profile of sporadic papillary thyroid cancer (PTC), whose aetiology is unknown, and PTC induced by internal radiation. So far, four transcriptomic studies comparing radiation-induced and sporadic thyroid cancer have been reported. However, no final conclusion has been drawn regarding the presence of a radiation signature, as either no difference was noted or the reported differences were not sufficiently convincing due to the low number of cases analysed or to the presence of confounding factors. The list of putative biological and clinical factors that may influence the PTC gene expression profile is long, but there are sufficient data reported in the literature to link expression profiles with differing pathological variants of PTC. The comparison of expression profiles in the tumour samples allows the search for a radiation signature, whereas the comparison of expression profiles of the normal contralateral tissues offers a substantial opportunity for assessing the existence of a susceptibility to radiation that could be responsible for tumour development. We have undertaken this analysis as part of a European Union-funded project, GENRISK-T. Gene expression profiles were investigated in tumours that have arisen in the population exposed to fallout from Chernobyl (i.e. born before 26 April 1986) and were compared with profiles of tumours of similar pathology arising in an age-matched population, residing in the same geographical area (same ethnicity) and born after 1 January 1987. RNA samples from these tumours and their contralateral normal tissues were obtained from the Chernobyl Tissue Bank. Several lines of evidence suggest that the predisposition to developing cancer after radiation exposure is variable in the general population and may be measurable from gene expression.