Overexpression of insulin-like growth factor-I receptor (IGF-IR) is seen in a multitude of human thyroid cancers and correlates with poor prognosis. However, recent studies suggest that low phospho-IGF-IR (pIGF-IR) expression rather than its overexpression may be an indicator of poorly differentiated disease. No previous study has evaluated the expression of pIGF-IR to determine if activation or loss of expression of this receptor is associated with thyroid tumor progression. Accordingly, a quantitative immunohistochemical (IHC) method was used to evaluate the clinico-pathological significance of pIGF-IR expression in archival samples of human thyroid carcinomas. Quantitative analysis of pIGF-IR levels revealed a significant difference in the median index of pIGF-IR between different histological subtypes of thyroid cancer (P < 0.001). Specifically, the median pIGF-IR index of differentiated thyroid cancers was significantly higher than the median index of other poorly differentiated thyroid cancer (P < 0.001). This was further confirmed in individual tumor sections of thyroid carcinoma where anaplastic and differentiated components co-existed. No significant difference was noted in the pIGF-IR index of tumors grouped by size or stage but a trend towards lower mean pIGF-IR index was noted in older patients. Our data indicates that pIGF-IR is upregulated in a majority of follicular thyroid carcinomas, suggesting it may be a potential target for therapy for patients with this disease. In addition, since low pIGF-IR expression was found to correlate with aggressive human thyroid carcinoma, it also suggests that IGF-IR may not be needed for progression of anaplastic thyroid carcinoma possibly because other cell signaling pathways are activated, obviating the need for IGF-IR signaling. However, more mechanistic studies would be necessary to substantiate the possibility that pIGF-IR may be important for differentiation of thyroid tissues and is lost with disease progression.