Abstract Drugs were determined by direct injection of plasma samples into a biocompatible extraction column. The column is based on particles with a biocompatible external surface and a hydrophobic internal surface. The pores of the particles are small enough to exclude the protein molecules; the drug molecules can penetrate the porous particle and are retained on the hydrophobic internal surface. Biocompatibility of the particles was obtained by reaction of the external surface with the human plasma protein α 1-acid glycoprotein. The surface within the pores of the particles contains hydrophobic C 8 or C 18 groups. The biocompatible extraction column was used in a fully automated system for the determination of ibuprofen, naproxen, propranolol, carbamazepine and phenytoin in plasma. No pressure increase was observed during the analysis of several hundred plasma samples. Plasma concentrations of propranolol in the range 4.5–125 ng/ml were determined with a precision (R.S.D.) of 0.75–1.8%. Linear calibration graphs were observed for the five drugs, and correlation coefficients of 1.0000 were obtained for four of the five model compounds.