The objective of the current work was to study an observed incompatibility between croscarmellose sodium and basic excipients in a tablet formulation. Significant dissolution slowdown was observed for alkaline tablet compositions of an acid-labile drug containing croscarmellose sodium (CCS) as a disintegrant. The severity of the dissolution slowdown was directly proportional to both the degree of alkalinity and the level of CCS in the tablet formulation. It is postulated that the ester cross-links in CCS were partially or fully hydrolyzed under basic conditions (pH values >9) forming by-products of increased water solubility. This increase in the level of water-soluble polymer can lead to the formation of a viscous barrier in the tablet upon moisture uptake, thus slowing down its dissolution. The dissolution slowdown was not observed for a similar alkaline tablet preparation containing crospovidone as a disintegrant.