RraA and RraB are recently discovered protein inhibitors of RNAse E, which forms a large protein complex termed the degradosome that catalyzes the initial step in the decay and processing of numerous RNAs in Escherichia coli. Here, we report that these E. coli protein inhibitors physically interact with RNAse ES, a Streptomyces coelicolor functional ortholog of RNAse E, and inhibit its action in vivo as well as in vitro; however, unlike their ability to differentially modulate E. coli RNAse E action in a substrate-dependent manner by altering the composition of the degradosome, both proteins appear to have a general inhibitory effect on the ribonucleolytic activity of RNAse ES, which does not interact with E. coli polynucleotide phosphorylase, a major component of the degradosome. Our findings suggest that these regulators of RNAse activity have a conserved intrinsic property enabling them to directly act on RNAse E-related enzymes and inhibit their general ribonucleolytic activity.