Low-dose metronomic chemotherapy is a promising therapeutic cancer treatment strategy thought to have an antiangiogenic basis. However, the advantages of reduced toxicity, increased efficacy in some cases, and ability to combine chemotherapy administered long term in this way with targeted therapies can be compromised by the empiricism associated with determining the optimum biologic dose (OBD). Using 4 distinct metronomic chemotherapy regimens in 4 different preclinical tumor models, including a hematologic malignancy, we established the OBD by determining the maximum efficacy associated with minimum or no toxicity. We then found each OBD to be strikingly correlated with the maximum reduction in viable peripheral blood circulating vascular endothelial growth factor receptor 2-positive (VEGFR-2+) endothelial precursors (CEPs). These results suggest that CEPs may serve as a pharmacodynamic biomarker to determine the OBD of metronomic chemotherapy regimens.