AbstractType I IFNs (IFN-αβ) constitute a family of cytokines that have important antiviral and immunoregulatory properties and have been successfully used in the treatment of a wide variety of diseases. There are 12 functional human IFN-α subtypes and one IFN-β subtype that signal through the common cell surface IFN-αβR. To date, virtually no information is available on the specificity of IFN-α responses in immune cells. In this study, Janus kinase/STAT signaling and transcriptional responses to selected IFN-α subtypes in human T cells and dendritic cells were analyzed. Evidence for IFN-α subtype and cell type specificity was found. Also, differences between kinetics of expression of IFN-stimulated genes (ISGs) and in the requirements of individual ISGs for additional signaling pathways were observed. In particular, IFN-γ-inducible protein-10 (IP-10), a key chemokine in Th1-type inflammatory diseases, was differentially regulated. In dendritic cells, it was highly induced by IFN-α2 and IFN-α21 but much less efficiently by IFN-α1. It was only marginally induced by these subtypes in T cells. In marked contrast to other ISGs analyzed, optimum induction of IP-10 was dependent on activation of p38 kinase(s). The observed variations (subtype-, cell type-, and ISG-related differentials) provide further insight into the complexity and plasticity of the IFN-αβ response. Furthermore, the novel observation that IFN-α1 poorly induces IP-10 is potentially of clinical importance, because this subtype may be more beneficial in cases where Th1-mediated side effects (e.g., exacerbation of autoimmune diseases) are not desirable.