The in vivo biocompatibility and biodegradation of crosslinked (co)polyethers with and without tertiary hydrogen atoms in the main chain and differing in hydrophilicity were studied by means of subcutaneous implantation in rats. After 4 days, 1 month, and 3 months postimplantation, the tissue reactions and interactions were evaluated by light microscopy (LM) and transmission electron microscopy (TEM). Poly(tetrahydrofuran) (poly(THF)), poly(propylene oxide) (poly(POx)), and poly(tetrahydrofuran-co-oxetane) (poly-(THF-co-OX)) were tested as relatively hydrophobic polyethers, and poly(ethylene oxide) (PEO) and a poly(THF)/PEO blend were used as more hydrophilic materials. In general, all polyethers showed good biocompatibility with respect to tissue reactions and interactions, with low neutrophil and macrophage infiltration, a quiet giant cell reaction, and formation of a thin fibrous capsule. For the relatively hydrophobic polyethers studied, the biostability increased in the order poly(POx) < poly(THF-co-OX) < poly(THF), probably indicating that the absence of tertiary hydrogen atoms has a positive effect on the biostability. Concerning the more hydrophilic materials, crosslinked PEO showed the highest rate of degradation, probably due to the mechanical weakness of the hydrogel in combination with the highest presence of giant cells as a result of the high porosity. A frayed surface morphology was observed after implantation of the crosslinked poly(THF)/PEO blend, which might be due to preferential degradation of PEO domains