PI3K/Akt signaling pathway plays critical role in many cell processes. There is indication that enhanced activation of PI3K/Akt cascade is implicated in thyroid tumors. Aim of this study was to evaluate the mutational status and expression of PI3K/Akt pathway mediators in papillary thyroid carcinoma in Greece. We evaluated the presence of mutations in PIK3CA (exons 9 and 20), AKT1 (exons 6-11), AKT2 (exons 6-11), AKT3 (exons 5-10), PTEN (exons 3-8), and PDPK1 (exons 4-10) genes in 83 papillary thyroid carcinomas by DNA sequencing. The expression levels of phospho-Akt and insulin-like growth factor I receptor (IGF-IR) were evaluated by immunohistochemistry. PIK3CA mutations were found in three samples. The analysis of AKT1 revealed one silent mutation in exon 9 (G726A) in 16 samples. One specimen carried an AKT3 mutation. One missense mutation was found in one sample in PTEN. No mutations were found in AKT2 and PDPK1. Increased levels of phosphorylated total Akt and IGF-IR were identified in some papillary cancers. Our findings indicate that PI3K/Akt signaling pathway is activated in some papillary tumors. However, mutations in genes coding most mediators of the pathway have not been proven to be the major modus of enhanced activation. These data suggest a potential role for PI3K/Akt-mediated signaling in papillary thyroid tumors.