Chronic inflammation is known to contribute to the origin of many cancer types, although the specific mechanisms of the association are not well understood. NLRX1, a mitochondrial NOD-like receptor protein, participates in inflammatory pathways. Recently we have shown that NLRX1 may contribute to the TNF-α induced cell death by affecting Casaspe-8 responses and ROS generation in mitochondria. In vitro experiments indicated that the expression of NLRX1 affects clonogenic ability in the presence of TNF-α. Here we show that inhibition of NLRX1 by RNA-interference substantially increases tumorigenicity of human tumor cell lines in nude mice. In contrast, an overexpression of NLRX1 notably decreases growth kinetics and tumor sizes, both in the presence and absence of TNF-α treatment. We conclude that the NLRX1 may be considered as a potential tumor suppressor.