The possible role of surface energy thermodynamics in mucoadhesion was investigated with Polycarbophil and pig intestinal mucosa. In separate experiments, the surface energy parameters of the substrate (mucosa) and the adhesive (polymer film) were determined by contact angle measurements on captive air/octane bubbles in three physiologically relevant test fluids (isotonic saline, artificial gastric fluid, and artificial intestinal fluid). Whereas the swollen Polycarbophil films were relatively hydrophilic as indicated by small water contact angles (22, 23, and 16 degrees), the water contact angles measured on mucosal tissue were significantly larger (61, 48, and 57 degrees). Hence, mucus was found to possess an appreciable hydrophobicity. The measured adhesive performance (force of detachment) between Polycarbophil and pig small intestinal mucosa was highest in nonbuffered saline medium, intermediate in gastric fluid, and minimal in intestinal fluid. In agreement with this trend, the mismatch in surface polarities between substrate and adhesive, calculated from the contact angle data, increased in the same order.