A quantitative clean-up procedure for drugs in plasma and urine in preparation for high-performance liquid chromatographic analysis is discussed. Samples are mixed with zinc sulfate, barium hydroxide, and acetonitrile (or methanol). Resultant solutions are clear and free of visible residue. Injections of over 420 samples of treated urine and 120 samples of treated plasma had no noticeable effect on pressure drop and column performance. An examination of the column head indicated no damage or discoloration to the packing. Baselines of the controls show no interference from endogenous compounds for the drugs studied. Precision study using cyclobenzeprine . HCl in plasma and urine by internal standard and external standard methods has within-run and day-to-day variations of under 5%. Drugs studied in urine and plasma are amiloride . HCl, cyclobenzeprine . HCl, cyproheptadine . HCl, diflunisal, indomethacin, phenylbutazone and sulindac. These drugs are selected for the various functional groups, their binding by proteins and their natural UV absorptivity. Conditions to improve recovery, advantages and limitations are discussed.