Histamine is a low-molecular-weight amine that plays several critical physiological roles, most notably in mediating the inflammation response. Reversed-phase HPLC analysis of histamine has been a challenge in the past due to the high polarity and poor retention. HILIC (hydrophilic interaction chromatography) offers a potential solution because of high polar analyte retention without the need of strong ion-pair reagents, which are not compatible with mass spectrometry (MS) detection and can cause signal suppression. Sample concentration and cleanup with solid phase extraction (SPE) further enhances the process and significantly increases throughput.