The presence of three drugs, dextromethorphan, amitriptyline and trimipramine in saliva were analyzed by mixed-mode chromatography on a Primesep D reversed-phase anion-exchange column. No sample preparation is required as proteins from saliva are not retained at these conditions and elute in the void of the column due to cation-exclusion effect. Both column and proteins are positively charged at current conditions. Mobile phase consists of ACN-water-formic acid and is compatible with LC/MS detection technique. This general HPLC method can be used for analysis of hydrophobic basic drugs in biofluids.