The aim of this study was to design oral controlled release lamivudine matrix tablets using hydroxypropyl methylcellulose (HPMC) as the retardant polymer, sodium alginate, acacia gum to study the effect of various formulation factors such as polymer proportion, polymer viscosity, and compression force on the in vitro release of drug. In vitro release studies were performed using (USP II) with paddle apparatus (basket method) in 900 mL of pH 6.8 phosphate buffer at 50 rpm. The release kinetics were analyzed using the zero-order model equation, Higuchi's square-root equation, and the Ritger-Peppas empirical equation. Compatibility of the drug with various excipients was studied. Increase in compression force was found to decrease the rate of drug release. Methematical analysis of the release kinetics indicated that the nature of drug release from the matrix tablets was dependent on drug diffusion and polymer relaxation and therefore followed non-Fickian or anomalous release. No incompatibility was observed between the drug and excipients used in the formulation of matrix tablets. The developed controlled release matrix tablets of lamivudine, with good initial release (32% in 4th hour) and extension of release up to 14 hours, can overcome the disadvantages of conventional tablets of lamivudine.