We describe an automated approach to analyzing whole plasma samples using online extraction without the need for an analytical column. A single restricted access material (RAM) column provided online extraction and pre-concentration of analytes while effectively removing proteins, salts and other biological materials found in the plasma sample matrix. The reduction in the plasma matrix enabled direct elution of the analytes from the extraction column to the mass spectrometer for selective detection. The precision of the method was evaluated using a proprietary therapeutic agent (Compound A) and was less than 5% over the range of 1-500ng/ml in spiked whole plasma, with an LOQ of 1ng/ml. A side-by-side comparison of RAM results from a pharmacokinetic study in rats was made with a traditional protein precipitation LC-MS method and a correlation of 0.993 was obtained between both methods. The injection-to-injection cycle time for the RAM method was 8min. Further automation was demonstrated by addition and mixing of the internal standard to all samples via an injection program of the autosampler.