Because of their regulatory properties on cellular proliferation and differentiation, regulators of G protein signaling (RGS) have been suggested as potential tumor suppressors. The aim of this study was to describe the normal pattern of RGS transcripts in the thyroid gland systematically and to elucidate their potential role in common thyroid pathologies. Real-time polymerase chain reaction (PCR) was applied to quantify mRNA expression of RGS transcripts in 10 hot thyroid nodules (HTN), 10 cold thyroid nodules (CTN), and corresponding surrounding tissues (ST). We have found that 9 of 13 tested RGS transcripts were expressed in the human thyroid gland. Expression of several RGS transcripts was altered in thyroid nodules compared to corresponding normal tissue. In HTN and CTN, mRNA transcripts of RGS 2, 9, and 12 were significantly downregulated. In contrast, mRNA expression of RGS 3, 6, 10 was differentially regulated in HTN and CTN compared to corresponding normal tissue. RGS 3 transcripts were significantly upregulated in CTN. RGS 6 transcripts were significantly downregulated in CTN. RGS 10 mRNA was significantly reduced in HTN. We therefore propose that downregulation of several RGS transcripts in thyroid nodules might contribute to tumor growth within the thyroid gland.