The Waters Xevo G2 QTof delivers exceptional levels of sensitivity, selectivity, in-spectrum dynamic range, speed of analysis, quantitative accuracy and exact mass performance. The Xevo G2‐oligo spectrometer system is coupled to an Acquity UHPLC system, providing ultra‐high sensitivity LC‐MS for the analysis of oligonucleotides. Analyses are completed by LC/MS using an ion-pairing reversed phase method where a mixture of HFIP and TEA is used to elicit retention of the polar polyanionic molecule. A RP‐HPLC purification step of the oligonucleotide sample needs to be performed before using the system. Oligonucleotide analysis requires deconvolution software for the identification of oligonucleotides.