Theophylline extended-release spheres were prepared by extrusion-spheronization of matrix granulations previously obtained by incorporation of the drug in melted Gelucire 50/02 or Gelucire 55/18. Hydrophobic Gelucire 50/02 behaved as an inert matrix and released theophylline very slowly compared with hydrodispersible Gelucire 55/18, which acted as a hydrophilic matrix. Extrusion-spheronization was more easily accomplished with Gelucire 50/02. The use of ethanol as a wetting fluid increased the rate of drug release noticeably with Gelucire 50/02 and less so with Gelucire 55/18. The use of castor oil, in conjunction with ethanol to slow down the solvent evaporation, improved extrusion and spheronization. Castor oil decreased the drug release rate with Gelucire 50/02 and increased it with Gelucire 55/18. These phenomena were explained by the different solubilities of theophylline, Gelucire 50/02, and Gelucire 55/18 in ethanol and castor oil. When microcrystalline cellulose (Avicel CL 611) was used in the granulation matrix, extrusion was improved. The best formulation was obtained with Gelucire 55/18 and Avicel CL 611 and was wetted by a mixture of ethanol and castor oil. Regardless of the formulation, the mechanism of theophylline release appeared to be via Fickian diffusion.