AbstractTo improve cell permeability, monomeric 3′‐deoxyadenosine (cordycepin) and antivirally active trimeric 3′‐deoxyadenylyl‐(2′–5′)‐3′‐deoxyadenylyl‐(2′–5′)‐3′‐deoxyadenosine (2′–5′)d3 (A‐A‐A); (cordycepin‐trimer core) were modified at the 2′‐O‐ or 5′‐O‐position by myristic, cholic, and folic acid = tetradecanoic, 3α, 7α, 12α ‐trihy‐droxy‐5β‐cholan‐24‐oic, and N‐{4‐{[(2‐amino‐3,4‐dihydro‐4‐oxopteridin‐6‐yl)methyl]amino}benzoyl}‐L‐glutamic acid, resp., linked by a 6‐aminohexamoyl spacer. Syntheses of the trimeric educts 21, 27, and 28 were performed by phosphoramidite chemistry, using β‐eliminating 2‐(4‐nitrophenyl)ethyl (npe), 2‐(4‐nitrophenyl)ethoxycarbonyl (npeoc) and (9H‐fluoren‐9‐yl)methoxycarbonyl (fmoc) groups which allow a deprotection by DBU in an aprotic solvent without harming the ester‐bounded conjugates, to give the products 24–26 and 31–33. The metabollically stable (2′–5′)A derivatives 26 and 33, covalently linked to folic acid either at the 2′‐terminus or at the 5′‐terminus of (2′–5′)d3′(A‐A‐A), respectively, are a new class of the anti‐HIV‐1 compounds. Inhibition of HIV‐1 reverse transcriptase (RT) activity by 26 and 33 was 45 and 81%, respectively. Only 33 activated recombinant, human RNase L by 35%.