A potential means to improve the ef®cacy of steric-blocking antisense oligonucleotides (ON) is to increase their af®nity for a target RNA. The grafting of cationic amino groups to the backbone of the ON is one way to achieve this, as it reduces the electro-static repulsion between the ON and its target. We have examined the duplex stabilising effects of introducing cationic phosphoramidate internucle-oside linkages into ON with a non-natural a-anomeric con®guration. Cationic a-ON bound with high af®nity to single-stranded DNA and RNA targets. Duplex stabilisation was proportional to the number of cationic modi®cations, with fully cationic ON having particularly high thermal stability. The average stabilisation was greatly increased at low ionic strength. The duplex formed between cationic a-ON and their RNA targets were not substrates for RNase H. The penalty in T m in¯icted by a single mis-match, however, was high; suggesting that they are well suited as sequence-speci®c, steric-blocking, antisense agents. Using a well-described target sequence in the internal ribosome entry site of the human hepatitis C virus, we have con®rmed this potential in a cell-free translation assay as well as in a whole cell assay. Interestingly, no vectorisation was necessary for the cationic a-ON in cell culture.