A large number of miRNAs have recently been discovered in plants and animals. Development of reverse genetic approaches that act to inhibit microRNA function would facilitate the study of this new class of noncoding RNA. Here we show that 2'-O-methyl oligoribonucleotides, but not 2'-deoxyoligonucleotides specifically inactivate the RNAi activity associated with miRNA-protein complexes in human cell extracts as well as in cultured human cells.