A simple, efficient and reproducible RP-HPLC method for determination of Esomeprazole in enteric coated tablet pharmaceutical dosage has been developed. The Separation was carried out on Zorbax SB C18 column (250 × 4.6 mm, 5 μm) column using buffer 6.8 g of potassium dihydrogen orthophosphate and 0.9 g of sodium hydroxide (NaOH) in 1000 ml of water (adjusted to pH 6.8 with 0.2 M NaOH). Buffer: Acetonitrile in the ratio of 40:60 v/v as diluent. The flow rate was 1.0 ml/min and effluent was detected at 280 nm. The retention times of esomeprazole was 3.2 min and the linearity ranges were found to be 50-150 μg/ml (r2=0.9990). The percentage relative standard deviation for accuracy and precision was found to be less than 2%. Hence, the method was effectively used for the regular analysis of esomeprazole in enteric coated tablet dosage form.