Review of recent mineral physics literature shows consistent trends for the influence of Fe and H2O on the bulk modulus (K0) of wadsleyite and ringwoodite, the major phases of Earth's mantle transition zone (410–660 km). However, there is little consensus on the first pressure derivative, K0′ = (dK/dP)P=0, which ranges from about 4 to >5 across experimental studies and compositions. Here we demonstrate the importance of K0′ in evaluating the bulk sound velocity of the transition zone in terms of water content and provide new constraints on the effect of H2O on K0′ for wadsleyite and ringwoodite by conducting a comparative compressibility study. In the experiment, multiple crystals of hydrous Fo90 wadsleyite containing 2.0 and 0.25 wt % H2O were loaded into the same diamond anvil cell, along with hydrous ringwoodite containing 1.4 wt % H2O. By measuring their pressure‐volume evolution simultaneously up to 32 GPa, we constrain the difference in K0′ independent of the pressure scale, finding that H2O has no effect on K0′, whereas the effect of H2O on K0 is significant. The fitted K0′ values of hydrous wadsleyite (0.25 and 2.0 wt % H2O) and hydrous ringwoodite (1.4 wt % H2O) examined in this study were found to be identical within uncertainty, with K0′ ~3.7(2). New secondary‐ion mass spectrometry measurements of the H2O content of these and previously investigated wadsleyite samples shows the bulk modulus of wadsleyite is reduced by 7.0(5) GPa/wt % H2O, independent of Fe content for upper mantle compositions. Because K0′ is unaffected by H2O, the reduction of bulk sound velocity in very hydrous regions of transition zone is expected to be on the order of 1.6%, which is potentially detectible in high‐resolution, regional seismology studies.