The liver and other organs are connected to each other through the bloodstream. Therefore, the connection between tissues is generally mediated by soluble molecules able to cross the endothelial wall of capillaries. We developed a multicompartmental device, multicompartmental bioreactor (MCB), designed to mimic the connection between different tissues in which crosstalk is mediated by soluble molecules transported through the blood. A comparative study of the crosstalk between hepatocytes (HepG2) and endothelial cells (human umbilical vein endothelial cells) in connected culture in the MCB and in a traditional static coculture system was performed by analyzing glucose consumption and secretion of albumin, urea, and nitric oxide. When hepatocytes and endothelial cells were cultured together, the production of albumin and urea increased, and the increase was higher in the MCB than in traditional static coculture. In spite of this enhanced metabolic activity, the crosstalk between hepatocytes and endothelial cell leads to decreased glucose consumption with respect to hepatocytes alone, both in static and in dynamic conditions. However, the dynamic connected culture has a higher rate of metabolite synthesis and secretion with respect to cocultures. This means a more efficient use of energetic substrates and enhanced hepatocyte function in the MCB.