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Chronic viral infections remain a global health burden. Here we study the role of immunosuppressive Transforming Growth Factor-Beta (TGF[Beta]) signaling on the immune response to different chronic infections in mice. We use genetic systems to modulate TGF[Beta]RII and SMAD4 adapter availability in a cell type specific and inducible manner similar to therapeutic approaches. We found that TGF[Beta] signaling minimally influenced Dendritic cell or Natural Killer cell responses early during infections. We further found TGF[Beta] signaling did not alter antiviral CD8 T cell number and function but did however suppress CD4 T cell differentiation during chronic viral infection. TGF[Beta] signaling on any of these cell types alone did not promote viral persistence. Importantly, we found TGF[Beta]/SMAD4 signaling did prevent hematopoietic-based pathology during chronic infection, which should be considered in therapy design to combat chronic infections