Zinc nger proteins (ZFPs) play important roles in plant responses to biotic and abiotic stresses. Through microarray analysis, an Oryza sativa L. multi-stress-responsive gene, OsMSR15, was identied and subsequently cloned from rice Pei'ai 64S (Oryza sativa L.). Expression of OsMSR15 was strongly up-regulated by cold, drought and heat stresses in different tissues at different developmental stages of rice. OsMSR15 contains two C2H2-type zinc nger motifs, a nuclear localization signal (B box), a Leu-rich domain (Lbox) and a conserved EAR-motif close to its C-terminus. The OsMSR15-GFP fusion protein was localized to the nucleus. Yeast-one hybrid assay showed that OsMSR15 possesses transcriptional activation ability. Expression of OsMSR15 in Arabidopsis conferred drought tolerance, and transgenic plants showed hypersensitivity to exogenous ABA during the seed germination and post-germination stages. Transgenic plants also showed higher levels of free proline, less electrolyte leakage and increased expressions of a number of stress-responsive genes, including LEA3, RD29A, DREB1A and P5CS1 under drought stress. The obtained results indicate that OsMSR15 is an important regulator involved in plant response to drought stress.