We found that there is an unknown aspect in serum RNases that cleaves ssDNA-dsRNA and ssRNA-dsRNA. In the first step, RNase cleaves the phosphodiester linkage between the first and second RNA, where the first one is connected to the single stranded RNA or DNA. In the second step, the ssRNA overhang attached siRNA is cleaved. When the 2' hydroxyl of the first RNA was replaced with methoxy, the cleavage did not occur. This RNase activity can be considered related to defense system against exogenous genetic materials. (C) 2012 Elsevier Inc. All rights reserved.