Abstract A critical point in the design of liquid metal blankets for fusion reactors is the accurate estimate of magnetohydrodynamic (MHD) pressure losses caused by the interaction between flowing breeder and magnetic field. In the Water-Cooled Lithium Lead (WCLL), the liquid metal (PbLi) is used as tritium breeder and carrier, whereas power extraction is delegated to water, thus allowing to minimize the breeder velocity. However, pressure drop for the PbLi loop is expected to remain significant due to high field intensity and direct electrical contact at fluid/wall interface. In this study, a comparative analysis between four alternative WCLL-DEMO configurations is performed to investigate the influence of blanket layout and piping system integration on this variable. Empirical and semi-empirical correlations, supported by numerical simulation results, have been used to estimate the baseline MHD loss, thus neglecting secondary contributions from viscous, inertial, and coupling effects. The larger contribution has been observed in the connection pipes, which are characterized by extensive length, high velocity, and large field gradients. Integration scheme with DEMO reactor is also a key factor, whereas breeding zone and manifold layout play secondary, albeit significant, roles in determining overall MHD loss. Adopting insulating elements in feeding and draining pipes should be carefully considered to reduce PbLi pumping requirements. Further numerical and experimental characterization of 3D MHD flow in manifolds and for coupling phenomena is vigorously suggested to reduce the uncertainty about blanket flow distribution and pressure loss estimate.