Development of effective drug regimens for AIDS can be aided by knowledge of the resistance patterns evoked by the agents. Recently foscamet(PFA)-resistant strains of HIV have been identified that exhibit increased susceptibility to AZT. Conversely, AZT resistance mutations can reverse PFA resistance. HIV strains that are coresistant to PFA and AZT have not yet been identified by in vitro selection or in treated patients. We therefore synthesized double conjugates of AZT-PFA which consist of a carboxyester with a long chain alcohol of 18 to 22 carbons and tested their antiviral activity against wild type and PFA- or AZT-resistant HIV-1. Plaque reduction assays were done in HT4-6C cells. Against the highly AZT-resistant strain A018-post, 3 -azido-3 -deoxy-5 -O(1-docosanyloxycarbonylphosphinyl)thymidine inhibited viral replication by 50% (EC 5 0 ) at 0.77 μM; by comparison the EC 5 0 values of PFA and AZT were 65 μM and 3.2 μM, respectively. Against the PFA-resistant HIV-1strain E89K, the double prodrug had an EC 5 0 of 0.17 μM versus >1000 μM for PFA and 0.01 μM for AZT. In HT4-6C cells, 3 -azido-3 -deoxy-5 -O(1-docosanyloxycarbonylphosphinyl)thymidine was cytotoxic (TC) at 320 μM. Antiviral activity and cytotoxicity will also be reported for similar prodrugs having either 18 or 20 carbon alkanols esterified at the carboxyl of AZT-PFA. We conclude that AZT-PFA lipid prodrugs may be useful for treatment of strains of HIV which have become resistant to AZT and PFA.