Purpose: Naproxen CR tablets have been obtained from its microspheres prepared by coprecipitation with Eudragit L100-55. The purpose of this work was to evaluate the main and interaction effects of deaggregating agent concentration. (X-1), compression pressure. (X-2) and amount of precipitating water. (X-3) on naproxen release. A secondary purpose was to obtain an optimized naproxen controlled release solid oral dosage form with a predictable 12 h drug release. Method: Eudragit L100-55 (10 g) was dissolved in 100 mL of ethyl alcohol, and 30 g of naproxen was dispersed in it with stirring. Purified water (100 mL, cooled to 4 degreesC) containing calcium chloride as a deaggregating agent was added to an alcoholic solution and homogenized. The mixture was filtered to obtain microspheres. Drug content analysis was performed spectrophotometrically at 332 nm. Tablets were prepared by compressing microspheres containing 500 mg of naproxen after adding 1% magnesium stearate. Dissolution was performed by the USP specifications of naproxen tablets. A 3-factor 3-level Box-Behnken design was employed to get 15 experimental runs. The independent variables used were X-1, X-2 and X-3. The dependent variables were dissolution at different time points with constraints on yield value and angle of repose of the microspheres, and hardness and thickness of the tablets. The dissolution constraints were placed such that the naproxen is released for 12 h by Higuchi's square root of time kinetics. Results: The mathematical relationship obtained between X-1, X-2, X-3 and the cumulative per cent of naproxen dissolved in 12 h with various constraints. (Y-5) was Y-5 = 2.39 - 1.13X(1) - 4.84X(2) - 2.12X(3) - 2.26X(1)X(2) - 0.5X(1)X(3) - 0.4X(2)X(3) + 2.4X(1)(2) - 0.4X(2)(2) (R-2 = 0.9). The equation shows that X-1, X-2 and X-3 affected the release inversely, and the most significant interaction was between X-1 and X-2. Y-5 has been maximized for optimization of naproxen release. Conclusions: Controlled release tablets of naproxen with predictable drug release characteristics were obtained by compressing its microspheres with Eudragit L100-55.