This study aimed to develop a protocol for blood product sample preparation enabling sustainable large-scale metabolic profiling using conventional RPC on a C18 column. This approach offers significant expansion of metabolic coverage in blood analysis, particularly for moderately hydrophobic metabolites, that are often poorly retained and detected using established RPC methods for lipid profiling or HILIC for polar LMWMs. However, C18 RPC analysis of plasma and serum samples suffer from the presence of proteins and lipids that, if not removed, can accumulate on the column in a RP system, negatively impacting the analysis of LMWMs through increased LC backpressure and ionization suppression. Figure exemplifies this challenge by showing C18 RPC+ chromatograms, pressure traces, and spectra of an untreated plasma sample compared to blank samples analyzed before and after. .