A new series of hitherto unknown 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) phosphonodiester derivatives incorporating carboxyesterase-labile S-acyl-2-thioethyl (SATE) moieties as transient phosphonate-protecting groups was prepared in an attempt to increase the oral bioavailability of the antiviral agent PMEA. We report here a direct comparison of the in vitro anti-HIV and anti-HSV activities as well as the in vitro stability between the bis(SATE) derivatives and the already known PMEA prodrugs, namely, bis[(pivaloyloxy)methyl (POM)]- and bis[dithiodiethyl (DTE)]PMEA. All of the compounds tested showed an enhanced in vitro antiviral activity compared to the parent PMEA. The bis(POM)- and bis(tBu-SATE)PMEA derivatives were the most effective. However, striking differences between these two compounds were found during the stability studies. In particular the bis(tBu-SATE)PMEA was found to be more stable than bis(POM)PMEA in human gastric juice and human serum, suggesting it could be considered as a promising candidate for further in vivo development.