Isothermal compressibility based on molecular dynamics simulations in a normal temperature and pressure (NTP)-Gibbs ensemble is estimated for five solvated globular proteins (bovine pancreatic trypsin inhibitor, trypsin, ribonuclease A, HEW lysozyme, and alpha -lactalbumin), as well as bulk water, using the TIP3P model. Protein intrinsic isothermal compressibilities were calculated from molecular total volume fluctuations and averages using the statistical definition of compressibility. A new and efficient method was developed for calculating protein total molecular volume based on an atomic van der Waals radius extension algorithm. The calculated isothermal compressibilities are in good agreement with experimental data (the correlation coefficient is 0.94). The main source of volume fluctuation is the free volume inside the protein, whereas variations in overlap of atomic van der Waals volume are less of a factor. Proteins with low packing density tend to have high compressibility, but packing density alone cannot explain the differences in the compressibility among globular proteins. A simple approach to assess the contribution to solution compressibility from hydration waters suggests small differences between hydration and bulk water compressibility. Estimated bulk water compressibility is in excellent agreement with experimental data. Two criteria for overcoming finite-size effects in bulk water molecular dynamics simulation are a simulation time longer than 300 ps and a system size larger than 260 water molecules.