The prognostic significance of tumor budding in colon cancer is unequivocally documented, and the recommendations of the International Tumor Budding Consensus Conference (ITBCC) are currently the accepted basis for its assessment. Up to now, it is unknown whether the general use of a supporting cytokeratin immunohistochemistry can improve the interobserver variability and prognostic significance. Six investigators with different levels of experience reassessed 229 cases of colon carcinoma (pT3/4, N+/−, M0) with a supporting cytokeratin immunohistochemistry. The results were compared to previous assessments, which have been performed only on H & E. Bd3 was significantly associated with the occurrence of distant metastases according to the assessments of three out of six investigators ( p < 0.05). Only one single investigator reached significant results concerning the cancer specific survival ( p = 0.01). The pairwise kappa values range between a poor and moderate level of agreement (range 0.17–0.45; median 0.21). In conclusion, the results show no superiority of the use of an additional cytokeratin immunohistochemistry compared to the conventional analysis on sole H & E slides. Therefore, the general supporting use of a cytokeratin immunohistochemical staining seems to be inadvisable in colon cancer in consideration of necessary resources and costs.