Although it is accepted that trifluoroacetic acid (TFA) can cause suppression of an analyte during LC/MS analysis, this paper presents a relatively sensitive gradient method that uses a TFA mobile phase for the improved quantification of small, polar drug-like compounds. The described method was developed in a discovery drug metabolism and pharmacokinetics (DMPK) laboratory for the screening measurement of compound concentrations to calculate PK parameters and CNS exposure of compounds from a chemical series that had poor chromatography under generic methods using formic acid mobile phase. The samples were collected by a Culex automated sampling unit, and the plasma proteins were precipitated by a Tecan robot in 96-well plates. After centrifugation, the supernatant was removed, dried down using a SPE-Dry unit, and the samples were reconstituted in aqueous buffer on the robot. The samples were analyzed on an Agilent LC/MSD using a 5-min gradient on a 5 cm phenyl column. No additional steps, such as the "TFA-fix", were necessary. Although sample batches were analyzed over 6h, no drift or degradation of signal was observed. The improved chromatography resulted in a method that was selective, rugged, and had a dynamic range from 5 to 20,000 nM, which was sufficient to quantitate low volume, serial plasma samples collected out to 8 h postdose.