Abstract The objective of present study is to develop the colon specific Didanosine enteric coated matrix tablets using release retardant polymer and pH sensitive polymer Eudragit L100 that retard the liberation of drug in upper gastro intestinal system and also show progressive release in colon. The influence of core tablet compositions, polymer combination ratios and coating levels on the in vitro release rate of Didanosine from coated tablets was investigated. The results showed that less than 10% drug was released in 0.1 N HCl within 2 hr, and about 90% of the drug was released in the pH 7.4 phosphate buffer for 24 hr. The in vitro drug release studies indicated that formulation F17 was a promising system to provide targeting of DDI to the colon. The release pattern of the above formulation was best fitted to zero-order model. Mechanism of drug release followed was non fickian (super case-II) transport mechanism. FTIR spectral studies showed that there is no interaction between the drug and excipients. The results of the present study have demonstrated that the pH-dependent tablet system is a promising vehicle for preventing rapid hydrolysis in gastric environment and improving oral bioavailability of Didanosine for the treatment of HIV infections.