Image guided computational fluid dynamics is attracting increasing attention as a tool for refining in vivo flow measurements or predicting the outcome of different surgical scenarios. Sharp interface Cartesian/Immersed-Boundary methods constitute an attractive option for handling complex in vivo geometries but their capability to carry out fine-mesh simulations in the branching, multi-vessel configurations typically encountered in cardiovascular anatomies or pulmonary airways has yet to be demonstrated. A major computational challenge stems from the fact that when such a complex geometry is immersed in a rectangular Cartesian box the excessively large number of grid nodes in the exterior of the flow domain imposes an unnecessary burden on both memory and computational overhead of the Cartesian solver without enhancing the numerical resolution in the region of interest. For many anatomies, this added burden could be large enough to render comprehensive mesh refinement studies impossible. To remedy this situation, we recast the original structured Cartesian formulation of Gilmanov and Sotiropoulos [Gilmanov A, Sotiropoulos F. A hybrid Cartesian/immersed boundary method for simulating flows with 3D, geometrically complex, moving bodies. J Comput Phys 2005;207(2):457–92] into an unstructured Cartesian grid layout. This simple yet powerful approach retains the simplicity and computational efficiency of a Cartesian grid solver, while drastically reducing its memory footprint. The method is applied to carry out systematic mesh refinement studies for several internal flow problems ranging in complexity from flow in a 90° pipe bend to flow in an actual, patient-specific anatomy reconstructed from magnetic resonance images. Finally, we tackle the challenging clinical scenario of a single-ventricle patient with severe arterio-venous malformations, seeking to provide a fluid dynamics prospective on a clinical problem and suggestions for procedure improvements. Results from these simulations demonstrate very complex cardiovascular flow dynamics and underscore the need for high-resolution simulations prior to drawing any clinical recommendations.