Stem-loop structures can protect upstream mRNA from degradation by impeding the processive activities of 3′–5′ exoribonucleases. The ability of such structures to impede exonuclease activity in vitro is insufficient to account for the stability they can confer on mRNA in vivo. In this study we identify a factor from Escherichia coli which specifically impedes the processive activity of the 3′–5′ exonuclease PNPase at stem-loop structures in vitro. This factor can, potentialiy, reconcile the apparent discrepancy between the ability of 3′ stem-loop structures to stabilize upstream mRNA in vitro and in vivo. Its mechanism of action, and possible role in regulating mRNA degradation, is discussed.