BackgroundAt different stages of the disease, biomarkers can help to determine disease progression and recurrence and provide a personalized indicator of therapeutic effectiveness. The serological identification of antigens by recombinant cDNA expression cloning (SEREX) has identified five SEREX antigens.ResultsCompared with healthy donors, anti‐FIRΔexon2 and anti‐SOHLH antibodies (Abs) in the sera of patients with colorectal cancer (CRC) were markedly higher. Furthermore, no correlation was noted between five SEREX antigens and the three tumor markers (CEA, CA19‐9, and anti‐p53 Abs), indicating that anti‐FIRΔexon2 Abs are an independent candidate marker for patients with CRC. Generally, the levels of anti‐FIRΔexon2 Abs combined with clinically available tumor markers were determined to be significantly higher compared with CEA, CA19‐9. Moreover, in early‐stage CRC, the levels of anti‐FIRΔexon2 Abs combined with existing tumor markers were higher than those of CEA, CA19‐9.ConclusionDue to the highly heterogeneous nature of CRC, a single tumor marker is unlikely to become a standalone diagnostic test due to its commonly insufficient sensitivity and/or specificity. Using a combination antibody detection approach of tumor markers for CRC diagnosis has the potential to be an effective approach. Therefore, the use of serum protein biomarker candidates holds promise for the development of inexpensive, noninvasive, and inexpensive tests for the detection of CRC.