The growth-inhibitory effects of type 1 interferons (IFNs) (IFNα/β) are complex, and the role of apoptosis in their antigrowth effects is variable and not well understood. We have examined primary murine interleukin-7-dependent bone marrow-derived pro-B cells, where IFNβ, but not IFNα, induces programmed cell death (PCD). IFNβ-stimulated apoptosis is the same in pro-B cells derived from wild type and Stat1 -/- mice. However, in pro-B cells from Tyk2-/- mice, where there is normal activation of Stat1 and Stat2, IFNβ-stimulated PCD is not observed. Loss of B cells in lymphocytic choriomeningitis virus-infected mice has been shown to be mediated through the expression of IFNα/β (1). In wild type mice infected with lymphocytic choriomeningitis virus, there is a greater loss of B cells in the bone marrow and spleen than in Tyk2-/- mice infected with the virus, suggesting that the expression of this kinase plays an in vivo role in IFNα/β-mediated PCD. In contrast to IFNβ-stimulated tyrosine phosphorylation of Stat1 and Stat2, Stat3 tyrosine phosphorylation is defective in Tyk2-/- pro-B cells, suggesting that this Stat family member is required for apoptosis. In support of this hypothesis, inhibition of Stat3 activation in wild type B cells reverses the apoptotic effects of IFNβ. Furthermore, expression of a constitutively active form of Stat3 in Tyk2-/- B cells partially restores IFNβ-stimulated PCD. These results demonstrate an important role of Tyk2-mediated tyrosine phosphorylation of Stat3 in the ability of IFNβ to stimulate apoptosis of primary pro-B cells.