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Background: Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Although early diagnosis and treatment is the most successful strategy for improving patient survival, feasible and sensitive blood biomarkers for CRC screening remain elusive. Methods: Sixty-five CRC patients and thirty-three healthy individuals were enrolled. Peripheral blood (PB) and tumor tissues from CRC patients, and PB from healthy individuals were subjected to immunophenotyping and phospho-flow analysis of cytokine-induced phosphorylated STAT (CIPS). Logistic regression was used as a classifier that separates CRC patients from healthy individuals. Results: The proportion of regulatory T cells was increased in PB from CRC patients compared to PB from healthy individuals (p < 0.05). Interestingly, peripheral T cells share several cytokine-induced phosphorylated STAT (CIPS) signatures with T cells from CRC tumor-sites. Additionally, a classifier was made using two signatures distinct between T cells from CRC patients and T cells from healthy individuals. The AUCs (area under curves) of the classifier were 0.88 in initial cohort and 0.94 in the additional validation cohort. Overall AUC was 0.94 with sensitivity of 91% and specificity of 88%. Conclusion: This study highlights that immune cell signatures in peripheral blood could offer a new type of biomarker for CRC screening.