The combined and comprehensive measurement of the metabolome and the exposome is challenging as the concentrations of metabolites, drugs, food constituents and environmental contaminants span approximately ten orders of magnitude and highly diverse classes of chemicals . Here, we present a rapid, highthroughput workflow, combining the analysis of endogenous metabolites and multiple classes of xenobiotics in human urine and plasma. The approach utilizes a dual column approach with a reversed-phase (RP) and a hydrophilic interaction liquid chromatography column (HILIC) being operated in parallel to cover polar compounds as well as the mostly non-polar xenobiotics. The exposome coverage was evaluated based on more than 200 highly diverse analytes comprising endogenous metabolites and xenobiotics to prove the power of the new method. The applicability to real-life samples was demonstrated by the analysis of urine samples of test sub-populations from Nigeria and Austria.