The purpose of the study is to perform the in vitro and in vivo evaluation of multi-layer film coatings for omeprazole. The system consists of drug-layered or drug-containing core pellets coated with salt (sodium chloride and disodium hydrogen phosphate), hydroxypropyl methyl cellulose (HPMC), and enteric film-coating layer, respectively. The drug-layered core pellets were prepared by a coating layer of omeprazole on inert pellet cores in fluidized bed coater. An in vitro/in vivo gastro-resistance study was conducted, and a dissolution study was performed in pH 7.4 phosphate buffer for omeprazole release. The multi-layer coated pellets were stable in gastric pH conditions and upper gastrointestinal (GI) tract in rats. Salt layer improved the drug stability, and its coating levels had little influence on the dissolution profiles of omeprazole. The rate of drug release was significantly delayed by HPMC layer. The salt layer could function as a separated layer, and substitute part of the HPMC layer and decrease the coating levels of HPMC. The bioavailability (AUC) of the multi-layer coated drug-layered and drug-containing pellets was 3.48+/-0.86 and 2.97+/-0.57 microg*h/ml, respectively. The drug-layered pellets with multi-layer film coatings not only provided delayed and rapid release of omeprazole, but also could provide a good stable property for omeprazole. It was confirmed that rapid in vitro drug release rate resulted in better absorption.