A method is presented to estimate the excess chemical potential of solutes in dense polymer microstructures with a combination of the thermodynamic-integration approach and Widom’s particle insertion from MD runs under constant NVT conditions on an atomistic level. The results obtained for pure water systems show good agreement with other calculated values and with experimental data. The calculated excess chemical potential of water dissolved in a wet polyamide(6) (PA-6) matrix is compared with the corresponding value of pure water. This gives a qualitative estimation of the equilibrium water content of amorphous PA-6.