Two tetra-p-tert-butyl-calix[4]arene species bearing one or two anti-HSV aciclovir units tethered via carbodiester linkages at the lower rim were synthesized as possible antiviral prodrugs. The amphiphilic properties of these derivatives were studied using Langmuir balance at the air–water and air–carbonate buffer interfaces; the monolayers formed were stable on both subphases. Monolayers formed with these molecules on a carbonate buffer subphase at pH 10 and 37 °C were then used for monitoring hydrolysis of the diester linkage. The release of free aciclovir of around 30% in 3 days was observed with both derivatives, as shown with HPLC.