MicroRNAs (miRs) are 21- to 23-nucleotide RNA molecules that regulate the stability or translational efficiency of target messenger RNAs of proteins involved in cell growth and apoptosis. miR-92 is part of the mir-17-92 cluster, which comprises members with an effect on cell proliferation. However, the role of miR-92 is unknown, and its targets have not been identified. Here, we describe a mechanism through which miR-92 contributes to regulate cell proliferation. Using a miR-92 synthetic double-strand oligonucleotide, we demonstrate that miR-92 increases 32D myeloid cell proliferation and 5-bromo-2-deoxyuridine (BrdU) incorporation and inhibits cell death. The effect is miR-92 specific since the miR-92 antagomir inhibits cell proliferation. Moreover, we show that miR-92 acts by modulating p63-isoform abundance through down-regulatation of endogenous DeltaNp63beta. Using luciferase reporters containing p63 3'UTR fragments with wild-type or mutant miR-92 complementary sites, we demonstrate that the wild-type 3'UTR is a direct target of miR-92. Finally, we observed that a miR-92-resistant DeltaNp63beta isoform (without 3'UTR) inhibits cell proliferation and parallels the effect of the antagomir. We conclude that one of the molecular mechanisms through which miR-92 increases cell proliferation is by negative regulation of an isoform of the cell-cycle regulator p63.