Lynch syndrome (LS), which is caused by germline mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS2), is the most common hereditary colorectal cancer syndrome, accounting for approximately 3% of all colorectal cancers. Recently, several authoritative international organizations recommend universal screening of LS for all newly diagnosed colorectal cancers. Universal screening of LS can be performed by immunohistochemistry (IHC) to identify deficient mismatch repair (dMMR) or by microsatellite instability (MSI) test. IHC has become the first choice for LS screening, due to its low detection cost, low requirements for testing equipment, availability in primary hospitals, and indication of potential mutant genes. However, due to the interference of impropriate tissue fixation, poor antibody quality, unskilled IHC staining techniques and unusual staining patterns, sometimes it is difficult to make a correct interpretation of IHC results. Influencing factors of interpreting IHC results include: cytoplasmic staining of tumor cell, weak staining of internal control cells, heterogeneity of tumor cells, special pathological manifestations (such as lymphocytic infiltration of tumor epithelium, signet ring cell carcinoma) and neoadjuvant chemoradiation. Avoiding the defects of IHC interpretation is critical to identify LS accurately, to reduce monitoring costs of the LS patients and their family members, and to avoid unnecessary anxiety for sporadic colorectal cancer patients. At the same time, due to its inherent defects in LS screening, IHC should not be used as the only method for LS screening. All currently available methods, including various screening standards, IHC, MSI, BRAF V600E mutation, MLH1 promoter methylation and germline gene mutation detection, should be comprehensively applied to make an accurate diagnosis of LS.