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Background: VEGF-A concentrations were measured in the blood of bevacizumab-treated cancer patients in previous studies, but a consensus has not formed that would develop VEGF-A into a clinical biomarker. Recently, methods to strictly distinguish between the VEGF-A isoforms have been developed but have not yet been applied to cancer patients undergoing bevacizumab treatment., Methods: An ELISA that strictly distinguishes between VEGF-A121 and VEGF-A165-the major isoforms of VEGF-A-and a commercially available ELISA for VEGF-A are used to determine the concentration of VEGF-A121, VEGF-A165, and VEGF-A in the blood of 12 patients with advanced colorectal cancer receiving bevacizumab therapy., Results: The serum and plasma concentrations of VEGF-A121 increased substantially post-bevacizumab administration; the median increase in serum was 860.8 pg/mL, 95% confidence interval (CI) [468.5, 1128.9], p = 0.0024, and in plasma was 808.6 pg/mL, 95% CI [748.7, 874.0], p = 0.00049. In stark contrast, VEGF-A165 after bevacizumab administration decreased in serum by a medium change of -73.8 pg/mL, 95% CI [-149.4, -10.2], p = 0.0034, with 83.3% of the post-bevacizumab concentrations falling below the high-accuracy threshold of 38 pg/mL; in plasma, all pre and post VEGF-A165 concentrations fell below this threshold. Concentrations of VEGF-A121 and VEGF-A165 in platelets did not change to a statistically significant degree. Adding recombinant VEGF-A121 (and -A165) or bevacizumab to plasma in patients post-bevacizumab administration increased or decreased, respectively, VEGF-A121 and VEGF-A165 levels. The increase in VEGF-A121 in plasma and serum after bevacizumab administration may be due to the dissociation of the complex of tumor-derived VEGF-A121 and bevacizumab when it moves from the stroma into the blood., Conclusions: The VEGF-A121 isoform has been uniquely demonstrated as a clear marker of bevacizumab therapy in both plasma and serum, motivating further research on pursuing these isoforms as biomarkers in cancer care., Competing Interests: No authors have competing interests., (Copyright: © 2024 Okawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)