Building upon the potent anti-HIV-1 activities observed for the 3-dimethylamino-4-benzylpyridinone 2, and the corresponding 4-aryloxypyridinone analogue 3, a concise and efficient route to the 3-iodo-4-aryloxypyridinones 14a-c (IOPY's) was developed. This involved reaction of the 4-hydroxy substituted pyridinone 10 with the requisite dichloroiodobenzene reagent 11. IOPY compound 14c is active at IC(50)=1-45 nM against wild type HIV-1 and a panel of six major simple/double HIV mutant strains.