Determining the status of DNA mismatch repair (MMR) proteins is crucial for patients because they may respond differently to specific treatments and have a better prognosis. We proposed a panel with only 2 antibodies to determine the status of the MMR proteins, improving costs, workload, and delivery of results. Patients with adenocarcinoma and MMR determination were reclassified using only the evaluation of PMS2 and MSH6. The diagnostic performance of the 2-antibody test (proposed panel) and 4-antibody (traditional panel) test was compared against the polymerase chain reaction study (reference standard). A total of 202 cases were identified. The predominant histological type was adenocarcinoma not otherwise specified, the predominant histological grade was 2, and 60.9% of the cases were found in clinical stage II. When comparing the diagnostic performance of the traditional panel of 4 antibodies against a panel of 2 antibodies, no statistically significant differences were found (sensitivity 95.35% vs. 90.7%; specificity 98.74% vs. 98.11%; positive predictive value 95.35% vs. 92.86%; negative predictive value 98.74% vs. 97.50%; area under the curve 0.970 vs. 0.944; p = 0.419).Analysis of MMR status determination with only 2 antibodies demonstrates that it is as effective as using 4 antibodies.