A major gap in our understanding of host response to virus infection is how the molecular signals are passed within infected cells. Tobacco mosaic virus-mediated programmed cell death in genotype NN tobaccos was used to evaluate the hypothesis that these molecular signals are transduced via reversible-protein phosphorylation. Nicotiana tabacum L. (genotype NN) confers a hypersensitive response at the site of virus infection when incubated at a permissive temperature. Activation of serine/threonine protein phosphatase correlated with the temperature-dependent induction of the death program. The serine/threonine protein phosphatase inhibitor okadaic acid inhibited the onset and extent of the hypersensitive response in vivo. Biochemical analysis indicates that protein phosphatase type 1 is activated early in the death program. This is the first indication that serine/threonine protein phosphatase is required in an early event of the host response to virus infection.