Background: Most of the focus on liquid biopsies for patients with colorectal cancers and other solid tumors has been on circulating tumor DNA (ctDNA). Circulating Tumor Cells (CTCs) are the other less talked about liquid biopsies. This is due to need for real-time processing and handling of CTCs, and is less conducive on previously banked samples. We took this prospective discovery endeavor to report in real-time CTC analyses using 2 very different platforms in patients with colorectal and other GI cancers. Methods: CTCs were evaluated using 2 platforms: RareCyte, which is simplistically based on density of CTCs and unbiased selection/identification for enumeration/biomarker analyses, and Parsortix, which is based on size/compressibility of CTCs. All patients signed written informed consent. Up to 4 serial draws were done for each patient (Total = 150 draws; 281 test results). CTCs were identified using standard definitions of nuclear/epithelial markers. À la carte we selected PD-L1, HER2, EGFR, Ki-67, and where adequate, confirmation with panel based single cell sequencing was also performed. Cell cultures were attempted for the Parsortix collections. Results: Patients with colorectal cancer (CRC) had the highest number of CTCs (Mean: 15.8; Median: 7.5). This was in sharp contrast to the number of CTCs in patients with pancreatic cancer (PC) (Mean: 4.2; Median: 3). At least a third of patients with CRC had at least 3 CTCs. Another 17.4% and 11.4% had at least 10, and at least 20 CTCs in CRC; while no patients with PC had more than 20 CTCs. CTCs in clusters were also common at baseline. In addition, we detected a significantly lower number of CTCs from patients receiving treatment versus those were not (Median 2.7 versus 0.7). Striking differences were also observed in CTCs for those with untreated/progressive disease versus those who had responding/stable disease (Median of 2.7 versus 0). Biomarker analyses on HER2/PD-L1/Ki-67/EGFR were feasible when CTCs were detected. There was overall agreement on CTCs detected on either platform. Where available, single cell sequencing data was concordant with clonal aberrations on sequencing. Conclusions: This is one of the largest prospective real-time endeavors in patients with colorectal and other GI cancers providing data on CTCs as liquid biopsies using 2 very different platforms. The descriptive insights gained from processing, enumeration, kinetics, timing of collection, biomarker analysis, costs, comparison across tumor types, attempts at cell culture, and single cell sequencing are of value for studies and investigators considering the use of CTCs in patients with colorectal and other GI cancers. While most of the focus is on ctDNA-based platforms, CTCs offer a different lens from a liquid biopsy standpoint that is complimentary and worth developing further.