Herpes simplex virus (HSV) virion host shutoff protein (vhs) destabilizes cellular and viral mRNAs. Previous work from several laboratories has indicated that vhs accelerates the turnover of most host mRNAs and provided evidence that at least some of these are degraded via endonucleolytic cleavage near regions of translational initiation followed by 5'-->3' decay. In contrast, several recent reports have argued that vhs is selective, preferentially targeting a subset of mRNAs including some that bear AU-rich instability elements (such as the stress-inducible IEX-1 mRNA). These reports concluded that vhs triggers deadenylation, 3' cleavage, and 3'-->5' decay of IEX-1 mRNA. However, we report here that HSV infection does not increase the rate of degradation of IEX-1 mRNA; rather, actinomycin D chase assays indicate that the transcript is stabilized relative to that in uninfected cells in both the presence and absence of functional vhs. Moreover, deadenylated but otherwise intact IEX-1 mRNA was readily detected in uninfected cells cultured under our experimental conditions, and its relative abundance did not increase following HSV type 1 (HSV-1) infection. We confirm that HSV infection increases the relative abundance of a discrete 0.75-kb 3'-truncated IEX-1 RNA species in a vhs-dependent manner. This truncated transcript was also detected (albeit at lower levels) in cells infected with vhs mutants and in uninfected cells, where it increased in abundance in response to tumor necrosis factor alpha, cycloheximide, and puromycin. We conclude that IEX-1 mRNA is not preferentially degraded during HSV-1 infection and that HSV-1 instead inhibits the normal turnover of this mRNA.