High-fidelity aerodynamic shape optimization based on the Reynolds-averaged Navier-Stokes equations is used to optimize the aerodynamic performance of a conventional tubeand-wing design, a hybrid wing-body (HWB), and a novel lifting-fuselage concept for regional-class aircraft. Trim-constrained drag minimization is performed on an HWB design, with an optimized conventional design serving as a performance reference. The optimized regional-class HWB yields no drag savings when compared to the conventional reference aircraft. Starting from the optimized HWB, an exploratory optimization with significant geometric freedom is then performed, resulting in a novel shape with a slender lifting fuselage and distinct wings. Based on this exploratory result, a new regional-class lifting-fuselage configuration is designed and optimized. With a span constrained by code 'C' gate limits and having the same wing-only span as the conventional reference aircraft, this new design produces up to 10% lower drag than the reference aircraft. The e↵ect of structural weight uncertainties, cruise altitude, and stability requirements are also examined. Nomenclature CTW Conventional tube-and-wing HWB Hybrid wing-body LFC Lifting-fuselage configuration x, y, z Streamwise, spanwise and vertical coordinates ⇤ Ph.D. Candidate, AIAA Student member,