PurposeTo develop a quantitative susceptibility mapping (QSM) method with a consistent zero reference using minimal variation in cerebrospinal fluid (CSF) susceptibility. Theory and MethodsThe ventricular CSF was automatically segmented on the R2* map. An L-2-regularization was used to enforce CSF susceptibility homogeneity within the segmented region, with the averaged CSF susceptibility as the zero reference. This regularization for CSF homogeneity was added to the model used in a prior QSM method (morphology enabled dipole inversion [MEDI]). Therefore, the proposed method was referred to as MEDI+0 and compared with MEDI in a numerical simulation, in multiple sclerosis (MS) lesions, and in a reproducibility study in healthy subjects. ResultsIn both the numerical simulations and in vivo experiments, MEDI+0 not only decreased the susceptibility variation within the ventricular CSF, but also suppressed the artifact near the lateral ventricles. In the simulation, MEDI+0 also provided more accurate quantification compared to MEDI in the globus pallidus, substantia nigra, corpus callosum, and internal capsule. MEDI+0 measurements of MS lesion susceptibility were in good agreement with those obtained by MEDI. Finally, both MEDI+0 and MEDI showed good and similar intrasubject reproducibility. ConclusionQSM with a minimal variation in ventricular CSF is viable to provide a consistent zero reference while improving image quality. Magn Reson Med 79:2795-2803, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine.