<p>In vitro models can recapitulate aspects of human liver diseases, thereby aiding therapeutic development. Dynamic interactions with vascular and immune cells contribute to disease progression in ways that are challenging to capture in the hepatic spheroid models commonly used for assessing facets of metabolism and disease. To address this, we developed a microphysiological system (MPS) featuring multicellular human hepatic spheroids physically integrated with self-organized microvascular networks. We demonstrate this MPS’s utility by modeling an insulin resistance state, where chronic exposure to disease-mimetic conditions yields altered hepatocyte metabolism, dysregulated vascular features, and increased inflammation state. We extend this system to capture disease-relevant changes in immune cell recruitment, showing that monocytes perfused through the vasculature will extravasate toward hepatic spheroids, with insulin-resistant samples exhibiting greater infiltration. Altogether, this vascularized liver MPS captures local hepatocyte-immune-microvascular interactions in an accessible microfluidic platform, enabling the study of clinically relevant immune-tissue interactions in complex metabolic disease.</p>