Hantaviruses cause two human diseases thought to be immune-mediated: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). We recently reported that the nucleocapsid (N) protein of HFRS-causing Hantaan virus (HTNV) inhibits tumor necrosis factor-alpha (TNF-alpha) activation of nuclear factor-kappaB (NF-kappaB). Here we measured the ability of other hantaviral N proteins to similarly interfere with the inflammatory process of TNF-alpha. We found that like HTNV N, the N proteins of HFRS-causing Seoul and Dobrava viruses inhibited TNF-alpha activation of NF-kappaB and translocation of the NF-kappaB p65 subunit, but did not interfere with degradation of inhibitor of NF-kappaB (IkappaB). In contrast, the HFRS-causing Puumala virus and the HPS-causing Andes and Sin Nombre viruses did not prevent TNF-alpha activation of NF-kappaB or nuclear translocation of p65. These studies provide evidence that hantaviruses differ in their abilities to interfere with host innate immune responses.