Numerous studies have focused on identifying prognostic biomarkers that reliably predict aggressive forms of papillary thyroid cancer at the early stages of disease and thus enable better treatment strategy. Most studies underline wide variation in the prevalence of BRAF V600E mutation in papillary thyroid cancer, which varies between 30% and 80% depending on geographic region and iodine consumption. Recent study reported that the loss of cleavage and polyadenylation specificity factor subunit 2 (CPSF2) is associated with increased cellular invasion and aggressive form of papillary thyroid cancer. The aim of this retrospective study was to determine the presence of BRAF V600E mutation and CPSF2 protein expression in papillary thyroid cancer archived specimens, thus defining a reliable biomarker for prognosis and progression of metastatic papillary thyroid cancer, which has recorded a significant and steady increase in the incidence. Based on the obtained results, we can conclude that the presence of the V600E mutation of the BRAF gene and the low expression of the CPSF2 protein cannot be considered independent predictive factors for the development of regional metastases. We found a significant association between the V600E mutation of the BRAF gene and occult metastases in the clinically negative neck. The results indicate that CPSF2 groups with an expression intensity of 2 and less have significantly more frequent relapses, and the group with a combination of a positive finding of the V600E mutation of the BRAF gene and expression of the CPSF2 protein <3+ has a significantly disease-free survival. Based on our research, we can conclude that determining the presence of BRAF mutation and CPSF2 protein expression in papillary thyroid cancer would improve the current guidelines and classification system for ATA risk assessment.