The oxidative stress-responsive kinase 1 (OSR1) is activated by WNK (with no K kinases) and in turn stimulates the thiazide-sensitive Na⁺-Cl^- cotransporter and the furosemide-sensitive Na⁺,K⁺,2Cl^- cotransporter thus contributing to regulation of cell volume, transepithelial transport, renal salt excretion and hence blood pressure. Little is known, however, about extrarenal functions of OSR1. The present study analysed the impact of decreased OSR1 activity on the function of dendritic cells (DCs), antigen-presenting cells linking innate and adaptive immunity. DCs were cultured from bone marrow of heterozygous WNK-resistant OSR1 knockin mice (osr^KI) and wild type mice (osr^WT). Cell volume was estimated from forward scatter, ROS-production from 2',7'-dichlorodihydrofluorescein-diacetate fluorescence, cytosolic pH (pH_i) from 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein fluorescence and Na⁺/H⁺-exchanger activity from Na⁺-dependent realkalinization following ammonium pulse. Cell volume and cytosolic pH were similar in osr^KI and osr^WTDCs, but Na⁺/H⁺-exchanger activity and ROS-production were higher in osr^KI than in osr^WTDCs. NHE1 inhibitor cariporide (10mM) decreased cell volume, intracellular ROS formation, Na⁺/H⁺-exchanger activity and cytosolic pH to a greater extent in osr^KI than in osr^WTDCs. LPS (1mg/ml) increased cell volume, Na⁺/H⁺-exchanger activity, and ROS-formation in osr^WTDCs but not in osr^KIDCs and blunted the difference between osr^KI and osr^WTDCs. Oxidative stress (10mM tert-butyl-hydroperoxide) increased Na⁺/H⁺-exchanger activity in osr^WT DCs but not in osr^KIDCs and reversed the difference between the genotypes. Cariporide virtually abrogated Na⁺/H⁺-exchanger activity in both genotypes and blunted LPS-induced cell swelling and ROS formation in osr^WTmice. In conclusion, partial OSR1 deficiency enhances Na⁺/H⁺-exchanger activity, alkalinizes cytosolic pH and fosters ROS-formation in dendritic cells.