Direct magnetic resonance phase images acquired at high field have been shown to yield superior gray and white matter contrast up to 10-fold higher compared to conventional magnitude images. However, the underlying contrast mechanism is not yet understood. This study demonstrates that the water resonance frequency is directly shifted by water-macromolecule exchange processes (0.040 ppm/mM for bovine serum albumin) and might be a major source of contribution to in vivo phase image contrast. Therefore, magnetic resonance phase imaging based on the proposed contrast mechanism could potentially be applied for in vivo studies of pathologies on a macromolecular level.