This study used acetaminophen as a model drug and investigated the effect of soluble excipients and super disintegrants on the dissolution difference between acidic and neutral media. Tablets with various formulas were prepared and their disintegration and dissolution in both acidic and neutral media were studied. A formula containing acetaminophen and crospovidone (Polyplasdone XL), with or without sucrose, did not show a big dissolution difference between acidic and neutral media, which correlates well with the disintegration study. In contrast, a formula containing acetaminophen, sucrose and croscarmellose sodium (Ac-Di-Sol) caused longer disintegration and slower dissolution in the acidic medium than those in the neutral medium. The difference of disintegration and dissolution in both media might be due to the interaction among ingredients.