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Human immunodeficiency virus type 1 (HIV‐1) impacts the activation state of multiple lineages of hematopoietic cells. Chronic HIV‐1 infection among individuals with progressive disease can be associated with increased levels of activated signal transducers and activators of transcription (STATs) in peripheral blood mononuclear cells. To investigate interactions between HIV‐1 and CD4+cells, activated, phosphorylated STAT proteins in nuclear extracts from lymphocytic and promonocytic cell lines as well as primary monocyte‐derived macrophages were measured. Levels of activated STATs increased six‐ to tenfold in HUT78 and U937 cells within 2 h following exposure to virions. The response to virus was dose‐dependent, but kinetics of activation was delayed relative to interleukin‐2 or interferon‐γ. Activation of STAT1, STAT3, and STAT5 occurred with diverse viral envelope proteins, independent of coreceptor use or viral replication. Envelope‐deficient virions had no effect on STAT activation. Monoclonal antibody engagement of CD4 identified a novel role for CD4 as a mediator in the activation of multiple STATs. Results provide a model for HIV‐1 pathogenesis in infected and noninfected hematopoietic cells.