In the present study, we show that (i) TNF is produced by T. cruzi-infected astrocytes and is upregulated by IFNγ stimulation prior to infection; (ii) TNF priming fuels astrocyte infection, accelerates amastigote multiplication and trypomastigote egression; (iii) TNF-primed infected astrocytes create a TNF- and IL-6-enriched inflammatory milieu; and (iv) TNF/TNFR1 signaling may fuel parasite infection. Here, IL6 is linked to parasitic infectious disease.