Translational repression and mRNA degradation are two major mechanisms for post-transcriptional regulation of gene expression. The detailed relationship between these two processes is not yet well established. Zinc-finger antiviral protein (ZAP) inhibits the replication of certain viruses, including human immunodeficiency virus 1, by binding directly to specific viral mRNAs and recruiting cellular mRNA degradation machinery to degrade the target mRNA. Here, we report that ZAP also inhibits the translation of target mRNAs by interfering with the interaction between translational initiation factors eIF4G and eIF4A. Furthermore, we provide evidence that translational repression is required for mRNA degradation and that blocking the degradation of target mRNAs does not affect ZAP-mediated translational repression. We conclude that ZAP can both repress translation and promote degradation of target mRNA, and that translational repression precedes and is required for mRNA degradation.