A generic method was developed for the fast determination of a wide range of drugs in serum or plasma. The methodology comprises generic solid-phase extraction, on-line coupled to gradient HPLC with tandem mass spectrometric detection (SPE-LC-MS/MS). The individual components of the SPE-LC-MS/MS system were optimized in an integrated approach to maximize the application range and minimize the method development time. The optimized generic SPE-LC-MS/MS protocol was evaluated for 11 drugs with different physicochemical properties. Good quantification for 10 out of 11 of the pharmaceuticals in serum or plasma could be readily achieved. The quantitative assays gave recoveries better than 95%, lower quantification limits of 0.2-2.0 ng/ml, acceptable precision and accuracy and good linearity over 2-4 orders of magnitude. Carry-over was determined to be in the range of 0.02-0.10%, without optimization. © 2003 Elsevier Science B.V. All rights reserved. Chemicals/CAS: caffeine, 30388-07-9, 58-08-2; carbamazepine, 298-46-4, 8047-84-5; paclitaxel, 33069-62-4; paracetamol, 103-90-2; procainamide, 51-06-9, 614-39-1; propranolol, 13013-17-7, 318-98-9, 3506-09-0, 4199-09-1, 525-66-6; ranitidine, 66357-35-5, 66357-59-3; sulfadiazine, 547-32-0, 68-35-9; sulfamerazine, 127-58-2, 127-79-7; theobromine, 83-67-0; theophylline, 58-55-9, 5967-84-0, 8055-07-0, 8061-56-1, 99007-19-9; Pharmaceutical Preparations