The mucoadhesive capacity of poly(2-hydroxyethyl methacrylate) (PHEMA) microspheres was studied in contact with Sprague-Dawley rat jejunum at pH=6 and at 22 degrees C. Dry PHEMA microparticles exhibited adequate mucoadhesive capacity, which was independent of nominal crosslinking ratio. When PHEMA microparticles were loaded with linear PEO chains of molecular weight 1000, the mucoadhesive capacity increased significantly, almost doubling. This behavior was attributed to a significant increase of the PEO chains penetrating across the mucosal tissue. However, very long pendant chains could have a detrimental effect on interpenetration, as was shown with PHEMA microparticles loaded with PEO chains of molecular weight 100 000 which exhibited only a limited mucoadhesive capacity. This was the result of extensive entanglements by the long PEO chains and impediment of chain mobility across the PHEMA/mucosal interface.