Sentinel node (SN) pathologic analysis shows great limitations related to reproducibility and challenges pathologists with respect to methodology and standardization. Recently, a new, highly specific and sensitive molecular procedure has been developed, based on cytokeratin 19 messenger RNA amplification, which allows for fast and effective intraoperative evaluation of the SN. Our aim in this study was to compare 2 arms for intraoperative evaluation: one study arm with 478 cases in which an exhaustive histopathologic procedure was performed and the other study arm with 211 cases that were analyzed using the new molecular method. Our results indicate that both methods similarly distinguish between benign and malignant lymph nodes but the type of metastasis is better defined and stratified by the molecular method. We conclude that the molecular method should be recommended for SN diagnosis because besides its high sensitivity, specificity, and operating room adequacy, it may allow for standardization for SN evaluation.