One common means to regulate protein activity is through phosphorylation. Protein phosphatases exist to reverse this process, returning the protein to the unphosphorylated form. The vast majority of characterized protein phosphatases target phosphoserine, phosphothreonine, and phosphotyrosine. A widely conserved phosphohistidine phosphatase was identified in Escherichia coli twenty years ago but remains relatively understudied. This bacterial protein is called signal inhibitory factor X (SixA) and belongs to a large family of phosphatases and phosphotransferases. Prior to this work, a single protein target of SixA was known: the E. coli histidine kinase ArcB. Here we analyze an ArcB-independent growth defect of a sixA deletion in E. coli. A screen for suppressors, analysis of various mutants, and phosphorylation assays indicate that SixA modulates phosphorylation of the nitrogen-related phosphotransferase system. This system is a widely conserved bacterial pathway that is regulated by nitrogen and carbon metabolism. It affects diverse aspects of bacterial physiology through the phosphorylation states of its protein components, EINtr, NPr, and EIIANtr, which receive phosphoryl groups on histidine residues. Despite over two decades of research, a mechanism for dephosphorylating this system has not been reported. Our results suggest a model in which SixA removes phosphoryl groups from the nitrogen-related phosphotransferase system by acting on NPr. This work uncovers a new role for the phosphohistidine phosphatase SixA and, through factors that affect SixA expression or activity, may point to additional inputs that regulate the nitrogen-related phosphotransferase system.