Human monocytes represent a heterogenous population of highly versatile immune cells. They are officially classified by their differential expression of the pattern recognition receptor CD14 and the Fc receptor CD16 into the major subset of CD14++CD16- classical and the two minor subsets of CD14++CD16+ intermediate and CD14+CD16++ non-classical monocytes, all of which have distinct genetic, phenotypical and functional properties. Classical monocytes show high phagoycytosis potential, non-classical monocytes produce highest amounts of pro-inflammatory cytokines, and intermediate monocytes are specialized in antigen presentation and express highest levels of pro-angiogenic molecules including TIE2. TIE2-expressing monocytes (TEMs) are selectively enriched in the intermediate subset and represent a major monocyte population in tumors which is proposed to promote cancer growth. Given the diverse nature of human monocytes and their development into tumor-associated macrophages, we hypothesized that the local disturbance in the tumor tissue may be reflected by circulating monocytes, either numerically or in terms of gene expression and function, and thus might precede alterations in macrophage infiltration or polarization in tumor tissue. We thus characterized monocyte subsets in blood and tissue of colorectal cancer (CRC) patients. Our results show that intermediate monocytes (but not TEMs) are significantly elevated in the blood of colorectal cancer patients and possess diagnostic potential for CRC diagnosis. Highest levels of intermediate monocytes were detected in localized disease and a stronger in vitro induction of these cells was observed in response to supernatants from primary as opposed to metastastic colon cancer cells. These findings support a role of intermediate monocytes in early tumor recognition by the innate immune system. In neoadjuvant cancer therapy for metastasized CRC, the frequency of blood intermediate monocytes rapidly increased after 2 therapy cycles and correlated with radiological treatment response, while their gene expression and migratory capacity remained unaltered. This increase of intermediate monocytes is likely to reflect the systemic response to the cytotoxic destruction of tumor tissue by chemotherapy. Notably, the blood levels of intermediate monocytes were also found to correlate with tumor infiltration by CD14+CD16+ monocytes in colorectal liver metastases (CLM). After liver resection for CLM, blood monocytes shifted further to remarkably high numbers of intermediate monocytes on postoperative day (POD) 1, which correlated with C-reactive protein values, likely reflecting the acute phase reaction. Sustained levels of intermediates on POD 3 signifcantly correlated with elevated liver enzymes, a marker of delayed liver regeneration. Intermediate monocytes, in particular TEMs, accumulated in subhepatic wound fluid by POD 3, which supports a role for TEMs in tissue regeneration. In conclusion, intermediate monocytes were found to exhibit substantial diagnostic and predictive marker potential for CRC patients.