Molluscum contagiosum virus (MCV) is a human poxvirus that causes abnormal proliferation of epithelial cells. MCV encodes specific molecules to control host defences, such as MC159L, which as previously shown prevents apoptosis induced by death receptors. However, unlike most poxviruses, MCV lacks a homologue to the E3L and K3L proteins of vaccinia virus, which are involved in the control of the key antiviral and pro-apoptotic dsRNA-dependent protein kinase, PKR. In this study, we analysed the relationship of MC159L to PKR. We found that MC159L is not a direct inhibitor of PKR since it does not associate with PKR and cannot block PKR-induced phosphorylation of eIF-2alpha. However, expression of MC159L inhibits apoptosis triggered by PKR through death receptor-mediated pathways. In addition, MC159L inhibits NF-kappaB activation induced in response to PKR. Expression of MC159L cannot counteract the PKR-mediated antiviral action in the context of a poxvirus infection, despite its ability to affect these signalling events. These findings show that MC159L is able to interfere with downstream events triggered by PKR in the absence of a direct physical interaction, and assign a role to MC159L in the control of some PKR-mediated biological effects.