We have investigated the behaviour of antisense oligonucleotides in rabbit reticulocytes. Both backbone-modified oligomers (methyl-phosphonate and phosphorothioate analogues), anomers of nucleotide units (alpha) and oligonucleotides linked to various ligands (intercalator, polylysine, dodecanol) were tested with respect to cellular uptake and inhibition of protein synthesis. Oligonucleotides added at an external concentration of 10 microM slowly entered the cell up to a concentration of a few hundred nanomolars. A large fraction of phosphorothioate analogues was found to be associated with the membrane. alpha-, methylphosphonate and phosphorothioate analogues remained intact during the incubation with reticulocytes although the latter were partly dephosphorylated. Antisense oligonucleotides were targeted against three different sites of the rabbit beta-globin mRNA: the 5' end of the message, the initiator AUG or the coding sequence. No specific effect on beta-globin synthesis was observed with any of the investigated compounds.