The thermodynamic miscibility, morphology, phase distribution, mechanical properties, surface properties, water sorption, bacterial adhesion and cytotoxicity of semi-interpenetrating polymer networks (semi-IPNs) based on crosslinked polyurethane (PU) and poly(hydroxyethylmethacrylate) (PHEMA) were studied to give an insight into their structure and properties. The free energies of mixing of the two polymers in semi-IPNs have been determined and it was shown that the values are positive and depend on the amount of PHEMA. This demonstrates that the components are immiscible, the extent of which is dependent upon variations in composition. The morphology of the semi-IPNs was analyzed with scanning electron microscopy and tapping mode atomic force microscopy (TMAFM). The micrographs of the semi-IPNs and TMAFM phase images indicated that distinct phase separation at the nanometer scale is observed. The mechanical properties reflect the changes in structure of semi-IPNs with composition. The stress at break increases from 3.4 MPa to 23.9 MPa, and the Young's modulus from 12.7 MPa up to 658.5 MPa with increasing amounts of PHEMA, but strain at break has a maximum at 40.4% PHEMA. The bacterial adhesion and cytotoxicity data suggest that semi-IPNs with PHEMA content above 22% may be used for biomedical material applications.