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Introduction: The ability to model the microenvironment of primary and secondary tumor sites is critical for advancing treatment options for metastatic breast cancer. There are currently no 3D tumor models that mimic the in vivo vascular geometry and tumor microenvironment for monitoring extravasation, tissue invasion, and colonization of secondary sites by metastatic tumors. In this study, we report on the development of a 3D tumor model with primary and secondary tumor sites, where metastatic breast cancer cells can escape the primary site, circulate in circulation, adhere to the vascular endothelium and subsequently invade distant tissues. Materials and Methods: Multiple synthetic tumor networks comprising primary and secondary tumor sites were developed using in vivo images and fabricated using soft lithography. Fluorescent dyes (FITC-dextran) was used to test the fluidic integrity while nano and micro-particles were used to test the porosity of the developed devices. Primary vascular endothelial cells were cultured in the vascular channels while GFP-labeled metastatic human breast cancer cell line (MDA-MB-231/GFP) or non-metastatic (MCF-7/GFP) was cultured in the primary tumor site in a 3D environment using Matrigel™. The vascular networks were perfused with endothelial cell media under physiological fluid flow conditions. Real-time monitoring of cellular growth, extravasation and invasion was performed using fluorescence microscopy over a four week period. Results and Discussion: Metastatic MDA-MB-231 breast cancer cells proliferated rapidly in the primary tumor site in contrast to non-metastatic MCF-7. Tumor cells were found to initiate a metastatic cascade as early as 7-10 days following growth in the primary site comprising of intravasation into the vascular channels, rolling and adhesion on the endothelium and extravasation into the secondary site. Significant differences were observed on the tumor behavior based on the flow profiles and morphology of the vascular networks. These results provide a unique perspective of the in vivo realism in an in vitro system for monitoring metastasis Conclusions: We have developed a 3D vascularized model for monitoring the invasive growth and the metastatic potential of tumors thereby mimicking the in vivo microenvironment of solid tumors. This model can be used to investigate tumor-endothelial cell interactions using a combination of real-time imaging techniques and screening of targeted therapeutics that may reduce the metastatic potential of tumors. Citation Format: Deborah Ramsey, Dustin Haithcock, Charles Garson, Ashley Gilbert, Ketan Bhatt, Balabhaskar Prabhakarpandian, Kapil Pant. 3D microfluidic tumor model for investigating metastatic tumor migration and colonization of secondary sites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-035.