Abstract Background Patients with stage II colorectal cancer (CRC) show considerable variability in prognosis. Circulating immune cells play a vital role in systemic tumor surveillance. This study aimed to determine the clinical significance of the frequency and phenotype of circulating immune cell subsets in patients with stage II CRC. Methods We applied a 37-marker-cell-lineage-agnostic panel to perform single-cell mass cytometry on peripheral blood mononuclear cells (PBMCs) from 73 patients with stage II CRC and 21 patients with stage III CRC. To categorize the stage II patients into consensus molecular subtypes (CMS), we performed RNA sequencing on tumor and adjacent normal tissues from 51 of the 73 patients. We then compared the immune cell phenotypes and frequencies based on tumor location and CMS classification in patients with stage II CRC. Wilcoxon test was employed to compare the mean frequencies of cell clusters between different tumor locations. Krustal–Wallis analysis with post-hoc Dunn test was used to assess differences across multiple CMS groups. Results Stage II CRC patients with left- and right-sided tumors, as well as in different CMS groups, exhibit significantly different tumor characteristics. Single-cell mass cytometry revealed profound interpatient variability in immune cell subpopulation distribution and phenotypes in PBMCs in stage II CRC. We identified unique T:monocyte complexes in the peripheral blood of patients with stage II CRC, with significantly higher frequencies in these patients compared to those with stage III CRC. Left- and right-sided stage II CRCs differed in peripheral immunity. Patients with right-sided CRC had significantly higher frequencies of circulating CD8+CD27-CD28- immunosenescent T cell subsets compared to patients with left-sided CRC. Significant variations were observed in the subpopulations of the T:monocyte complex, T cells, and monocytes across different CMS groups Patients with CMS1 tumors (immune-active) exhibited significantly higher frequencies of CD4+ central memory and CD8+ terminal effector T cell: classical monocyte complexes, as well as CD8+ terminal effector T cells in the circulation. Conclusions The frequency and phenotype of circulating immune cells are influenced by tumor side and CMS subtypes in stage II CRC. These observations provide a basis for further investigation into the mechanisms linking tumors and systemic immunity.