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Derangements of one-carbon metabolism have been related to the development of chronic diseases. Metabolic profiling as part of epidemiological studies in this area should include intermediates involved in the transfer of one-carbon units, cofactors for the relevant enzymes and markers of inflammation, kidney function and smoking.We established five platforms that measured 6–16 analytes each. Platforms A (gas chroma-tography-mass spectrometry; GC-MS) and B (gas chromatography-tandem mass spectrometry; GC-MS/ MS) involved methylchloroformate derivatization of primary amines, thiols and carboxylic acids. Platform C determined basic compounds by liquid chromatography-tandem mass spectrometry (LC-MS/MS), using an ether-linked phenyl reversed-phase column. Platforms D and E (LC-MS/MS) exploited the efficient ionization and high sensitivity obtained for a wide range of analytes, using a mobile phase containing a high concentration of acetic acid. The chromatographic run times ranged from 3 to 8 min.The analyte concentrations ranged from 0.2 nmol/L to 400 μmol/L. Platforms A and B both measured methylmalonic acid, total homocysteine and related amino acids. Platform B also included sarcosine, cystathionine, tryptophan and kynurenine. Platform C was optimized for the measurement of choline and betaine, but also included arginine, asymmetric and symmetric dimethylarginine and creati-nine. A diversity of low abundance compounds mainly occurring in the nanomolar range were measured on platform D. These were vitamin B2 and B6 species, neopterin, cotinine and tryptophan metabolites. Platform E measured folates and folate catabolites.Approximately 40 analytes related to one-carbon metabolism were determined in less than 1 mL of plasma/serum using five complementary analytical platforms. As a method control, several metabolites were measured on two or more platforms. Logistics and data handling were carried out by specially designed software. This strategy allows profiling of one-carbon metabolism in large-scale epidemiological studies.