Purpose: The incidence of hyperplastic thyroid nodular disease has been consistently rising over the last decades. In addition, unsuspected papillary thyroid carcinoma (PTC) can be found in up to 34% of patients operated for benign thyroid lesions. PTC tends to occur multi-focally and is commonly of polyclonal origin. We set out to test the hypothesis that in benign thyroid disease, a unique genetic signature can already be identified in the benign pathology, which is associated with a susceptibility of the thyroid tissue to neoplastic transformation in the context of additional growth promoting stimuli. Patients and Methods: We obtained a set of 23 samples from patients with multinodular goiter (MNG), 12 of whom also harbored an unsuspected PTC. We used global gene expression analysis to evaluate for dissimilarities in the gene expression patterns between these two groups. We also compared these patterns to the profiles of 3 normal thyroid and 7 PTC samples. Results: We were able to accurately distinguish between hyperplastic nodules of patients with multinodular goiter and those that were associated with a PTC. One of the strongest differentially expressed genes, CDC42, has been implicated to respond to environmental factors such as UVB radiation and might point to novel factors contributing to PTC genesis in the setting of pre-existing benign proliferative disease. Conclusion: While the comparison between histologically identical samples cannot distinguish the two groups of goiters, unsupervised or supervised approaches allowed us to identify a molecular signature associated with PTC susceptibility in multinodular goiter.