Background: This study aimed to investigate the feasibility of preparation of sustained-release chlorpheniramine maleate (CPM) pellets based on Compritol® as a lipid matrix and evaluation of the affecting factors on pellet properties. Method: Using the D-optimal experimental design, different pellet formulations containing various amounts of CPM, Compritol® and Avicel were prepared by the wet extrusion-spheronization method. Then the pellets were cured at 40, 65 and 90 ̊C for 4 and 8 h to study the effect of the thermal process. The physicomechanical properties of the pellets were investigated in terms of particle size distribution, pelletization yield, mechanical strength, aspect ratio and sphericity. To investigate the possible interaction of CPM and Compritol®, as well as to evaluate the morphology and surface characteristics of the pellets DSC and SEM were used, respectively. Also, to investigate the drug release rate from pellets the dissolution test was carried out and mean dissolution time (MDT) was calculated to compare different formulations. Results: The results showed that the curing process up to 65 °C improves the strength of the pellets. However, increasing the curing temperature from 65 to 90 °C and also increasing the curing time from 4 to 8 h did not have a significant effect on the strength of the pellets but increased the drug release rate of pellets. Increasing the amount of the drug or decreasing Compritol® in the matrix of pellets leads to a larger particle size with greater mechanical strength. All formulations of the pellets had an aspect ratio and sphericity of about 1.1 and 0.9 respectively, which indicates the spherical shape of the pellets as shown by SEM. DSC thermograms indicate the reduction of the crystallinity or the change of the crystalline form of the drug to amorphous during the pelletization process. Conclusion: The results revealed the feasibility of preparing lipid-based sustained-release matrix pellets using the wet extrusion-spheronization method. The optimal formulation in terms of physicomechanical properties and release rate was the formulation containing 8% CPM, 67% Compritol® and 25% Avicel, which were dried at 40 ° C for 4h and released about 90% of the drug within 12 h.