Asthma is considered as the most relevant pulmonary disease which is located at bronchial airways and oral theophylline is one of the most prescribed drugs for its treatment as it is inexpensive. However, the frequency of theophylline side-effects has recently reduced its usage. Inhaled theophylline has not been successful either, mostly due to the lack of retention in the airways and irritation. In this study, theophylline was encapsulated in mucoadhesive starch microspheres using an inverse emulsion method. Glutaraldehyde was applied as the cross-linker for some of starch-derived microspheres. Cross-linking reaction was studied by means of the FTIR. A central composite face (CFC) design was used to optimize manufacturing conditions in order to obtain the highest drug entrapment yield and ideal aerodynamic diameter range of 5-11 mu m at which bronchial deposition is maximum. Optimized microspheres were successfully reproduced using the model provided by CFC design and their experimental aerodynamic diameter and drug entrapment yield were in good correlation with predicted values. Drug release of optimized microspheres was measured in phosphate buffer solution. Both cross-linked and uncross-linked microspheres showed biphasic Fickian type drug release (Higuchi Model). These new formulations may recover the role of this valuable drug in asthma management.