Antiviral defenses can sense viral RNAs and mediate their destruction. This presents a challenge for host cells since they must destroy viral RNAs whilst sparing the host mRNAs that encode antiviral effectors. Here we show that highly upregulated interferon-stimulated genes (ISGs), which encode antiviral proteins, have distinctive nucleotide compositions. We propose that self-targeting by antiviral effectors has selected for ISG transcripts that occupy a less self-targeted sequence space. Following interferon stimulation, the CpG-targeting antiviral effector ZAP reduces the mRNA abundance of multiple host transcripts, providing a mechanistic explanation for the repression of many (but not all) interferon-repressed genes (IRGs). Notably, IRGs tend to be relatively CpG-rich. In contrast, highly upregulated ISGs tend to be strongly CpG-suppressed. Thus, ZAP is an example of an effector that has not only selected compositional biases in viral genomes but appears to have notably shaped the composition of host transcripts in the vertebrate interferome.