The eIF2 alpha protein plays a critical role in the regulation of translation. The production of double-stranded RNA (dsRNA) during viral replication can activate protein kinase R (PKR), which phosphorylates eIF2 alpha, leading to inhibition of the initial step of translation. Many viruses have evolved gene products targeting the PKR-eIF2 alpha pathway, indicating its importance in antiviral defense. In the present study, we focused on alternations of PKR-eIF2a pathway during human herpesvirus 6A (HHV-6A) infection while monitoring viral gene expression and infectious viral yields. We have found increased phosphorylated PKR as well as phosphorylated eIF2 alpha coincident with accumulation of the late gp82-105 viral protein. The level of total PKR was relatively constant, but it decreased by 144 h postinfection. The phosphorylation of eIF2a led to a moderate increase in activating transcription factor 4 (ATF4) accumulation, indicating moderate inhibition of protein translation during HHV-6A infection. The overexpression of PKR led to decreased viral propagation coincident with increased accumulation of phosphorylated PKR and phosphorylated eIF2a. Moreover, addition of a dominant negative PKR mutant resulted in a moderate increase in viral replication. HHV-6A exhibits relatively low efficiency of propagation of progeny virus secreted into the culture medium. This study suggests that the replicative strategy of HHV-6A involves a mild infection over a lengthy life cycle in culture, while preventing severe activation of the PKR-eIF2 alpha pathway. IMPORTANCE Human herpesvirus 6A (HHV-6A) and HHV-6B are common, widely prevalent viruses, causing from mild to severe disease. Our study focused on the PKR-eIF2 alpha stress pathway, which limits viral replication. The HHV-6 genome carries multiple genes transcribed from the two strands, predicting accumulation of dsRNAs which can activate PKR and inhibition of protein synthesis. We report that HHV-6A induced the accumulation of phosphorylated PKR and phosphorylated eIF2 alpha and a moderate increase of activating transcription factor 4 (ATF4), which is known to transcribe stress genes. Overexpression of PKR led to increased eIF2 alpha phosphorylation and decreased viral replication, whereas overexpression of a dominant negative PKR mutant resulted in a moderate increase in viral replication. These results suggest that the HHV-6A replication strategy involves restricted activation of the PKR-eIF2 alpha pathway, partial translation inhibition, and lower yields of infectious virus. In essence, HHV-6A limits its own replication due to the inability to bypass the eIF2 alpha phosphorylation.