Poly(N-isopropylmethacrylamide) (PNIPMAM) is a thermoresponsive polymer, exhibiting lower critical solution temperature (LCST) behavior in an aqueous solution. We investigate the temperature-dependent phase behavior of PNIPMAM solutions in D2O using turbidimetry, differential scanning calorimetry (DSC), small-angle and very small angle neutron scattering (SANS and VSANS), and Raman spectroscopy, covering a large concentration range, and compare the results from PNIPMAM with the findings from its analogue poly(N-isopropylacrylamide) (PNIPAM). We find that the PNIPMAM chains only dehydrate 2–3 °C above the macroscopic cloud point temperature, TCP. Even in the one-phase state, loosely packed, large-scale inhomogeneities and physical cross-links are observed, and the chain conformation of PNIPMAM is more compact than the one of PNIPAM. This is attributed to the attractive intermolecular interactions between the hydrophobic moieties. The phase transition of PNIPMAM is broader than the one of PNIPAM. Upon heating to the two-phase state, the PNIPMAM chains collapse and form mesoglobules. These are larger and more hydrated than those for PNIPAM. This is attributed to the steric hindrance caused by the additional methyl groups, which weaken the intrapolymer interactions in the two-phase state. Thus, the methyl groups in the backbone of the PNIPMAM chains have a significant impact on the hydration and the structural behavior around the phase transition.