Electrospray ionization mass spectrometry (ESI-MS) coupled to reverse-phase high performance liquid chromatography (RP-HPLC) has emerged as one of the most powerful techniques for the analysis of biochemical and pharmaceutical compounds. Trifluoroacetic acid (TFA) is a commonly used additive in HPLC and LC–MS analysis of basic compounds. However, TFA is known to suppress the ESI signals of analytes due to its ability to form strong gas-phase ion pairs with positively-charged analyte ions. This ion-pairing process “masks” the sample positively-charged analyte ions/cations from the ESI-MS electric field by rendering them “neutral”. To overcome the signal suppression effect of TFA on basic compounds, we studied a simple and very effective means of minimizing the negative effect of TFA in analysis of aniline, caffeine, arginine and glutamine by addition of acetic acid or propionic acid to analyte solution containing 0.05% TFA. A factor of up to two fold signal enhancement (for arginine and glutamine) and full original signal recovery (for caffeine) were achieved.