In this study, we developed a computer simulation to demonstrate the importance of reference in QSM. The results show that QSM values are substantially affected by spatial coverage for reconstruction. Only when the data are referenced using a neighboring region, the QSM results provide correct susceptibility values. Additionally, we suggest a new “differential ROI” reference method. This approach reports the susceptibility value as a difference between two (neighboring) ROIs. We demonstrate this new approach for a Parkinson’s disease patient study.