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Simple Summary: Although papillary thyroid carcinoma (PTC) is generally a highly curable disease, there is a small subgroup of PTC cases that behaves more aggressively, with high rates of disease recurrence, tumor progression and distant metastases. These patients need to be accurately identified for an appropriate, more-aggressive therapeutical approach. BRAFV600E mutation is the most prevalent genetic event in PTC. However, its role as a prognostic factor remains unclear. Herein, we aimed to assess the prognostic value of BRAFV600E mutation as a single factor, as well as in synergic interaction with other demographic and pathological risk factors in a series of 127 PTCs. Our results highlight a significant impact of BRAFV600E mutation on event-free survival among PTC patients. Nevertheless, BRAFV600E mutation status should not be used as an independent predictive factor in PTC patients, but rather should be integrated in the context of other clinicopathological risk factors. We aimed to evaluate the prognostic value of BRAFV600E mutation in a series of 127 papillary thyroid carcinoma (PTC) cases as a single factor, and in synergic interaction with other standard risk factors. BRAFV600E mutation was assessed by real-time PCR. Event-free survival (EFS) was calculated between the date of the first evaluation and the date of occurrence of an adverse event or the date of the last known status. The prevalence of BRAFV600E mutation was 57.2%. The Kaplan–Meier analysis showed a significant reduction of EFS among cases harboring BRAFV600E mutation compared to non-mutated cases (p = 0.010). In addition, BRAFV600E mutation was found to better predict adverse outcomes when associated with the following risk factors: age ≥ 55 years old (p < 0.001), male gender (p < 0.001), conventional (p = 0.005) and tall cell (p = 0.014) histology, tumor size > 40 mm (p = 0.001), extrathyroidal extension (p = 0.001), multifocality (p = 0.001) and lymph node metastasis (p < 0.001). In univariate analysis, a 3.74-fold increased risk for a reduced EFS (p = 0.018) was found for BRAFV600E-mutated cases, but no increased risk was further confirmed by multivariate analysis. Our results highlight that BRAFV600E mutation cannot be used alone as an independent predictive factor in PTC patients, but is prognostically valuable if integrated in the context of other clinicopathological risk factors. [ABSTRACT FROM AUTHOR]