As part of our studies on the anti-HIV activities of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) and their 'ProTides', we have prepared and evaluated the anti-HIV activity of a range of d4U and ddU aryl triester phosphoramidates. Besides elucidating SAR characteristics, we performed molecular modelling studies on both d4U and ddU in order to probe the first phosphorylation step required for the activation of these two nucleoside analogues. Overall, the application of the phosphoramidate approach turned the inactive ddU to a moderately active anti-HIV agent, while this was not the case with d4U. Enzymatic assays investigating the metabolism of d4U phosphoramidates revealed an efficient cleavage of the phosphoramidate motif to release the d4U monophosphate. Thus, a poor second and/or third phosphorylation step may be the most likely reason for the virtual lack of anti-HIV activity in this case.