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The aim of the current study was to design oral controlled release mucoadhesive compressed hydrophilic matrices of atenolol and to optimize the drug release profile and bioadhesion using response surface methodology. Tablets were prepared by direct compression and evaluated for bioadhesive strength and in vitro dissolution parameters. A central composite design for 2 factors at 3 levels each was employed to systematically optimize drug release profile and bioadhesive strength. Carbopol 934P and sodium carboxymethylcellulose were taken as the independent variables. Response surface plots and contour plots were drawn, and optimum formulations were selected by feasibility and grid searches. Compressed matrices exhibited non-Fickian drug release kinetics approaching zero-order, as the value of release rate exponent (n) varied between 0.6672 and 0.8646, resulting in regulated and complete release until 24 hours. Both the polymers had significant effect on the bioadhesive strength of the tablets, measured as force of detachment against porcine gastric mucosa (P<.001). Polynomial mathematical models, generated for various response variables using multiple linear regression analysis, were found to be statistically significant (P<.01). Validation of optimization study, performed using 8 confirmatory runs, indicated very high degree of prognostic ability of response surface methodology, with mean percentage error (±SD) as −0.0072±1.087. Besides unraveling the effect of the 2 factors on the various response variables, the study helped in finding the optimum formulation with excellent bioadhesive strength and controlled release.