Papillary thyroid carcinoma (PTC) is frequently multifocal, which can represent either intraglandular spread from a single primary tumor or multiple synchronous primary tumors (MSPTs). To distinguish and characterize these entities, we investigated whether multifocal PTCs contain genetically similar or different mutations and have particular histopathologic characteristics. In 60 cases of PTC with 2 to 4 discrete tumor foci, each focus was tested for BRAF, NRAS, HRAS, and KRAS point mutations and RET/PTC1 and RET/PTC3 rearrangements and analyzed for various histopathologic features. Overall, BRAF mutations were found in 43% of tumors, RAS in 27%, and RET/PTC in 2%. Four different patterns of mutation occurrence were identified: (i) 2 foci containing different mutations (30%); (ii) 1 tumor containing a mutation and another carrying no mutations (32%); (iii) both/all tumors containing the same mutation (25%); (iv) all tumors having no mutations (13%). The 30% of cases with 2 different mutations represent a group of tumors that are unequivocally MSPT. These tumors more commonly occurred in different lobes, although they could be located as close as 0.6 cm from each other. Moreover, MSPTs typically demonstrated distinct histologic variants/microscopic features, were encapsulated or had a smooth border, and showed no microscopic peritumoral dissemination. In conclusion, we demonstrate that at least 30% of multifocal PTCs represent unequivocal MSPTs that develop through distinct molecular alterations and that as many as 60% of multifocal PTCs are likely MSPTs. Histopathologically, MSPTs are typically located in different lobes, have distinct growth patterns, and do not show microscopic peritumoral dissemination.