A selective and highly reproducible, multi-column HPLC method is described for the analysis of the following cardiovascular drugs: lidocaine, pindolol, metoprolol, oxprenolol, diltiazem and verapamil, in serum. Column-switching devices are employed in combination with advanced separation media technologies for the automated analysis of samples containing complex matrices. The method consists of on-line sample clean-up using a restricted access sorbent, HPLC analysis of the drugs on a microsphere non-porous silica RP-18 column, and front-cutting to perform the chiral separation of pindolol enantiomers on a second HPLC system. Simultaneous control of the two HPLC systems and data analysis is achieved from a single centralized software. The R.S.D. values of the peak areas for spiked serum are less than 1% for metoprolol and oxprenolol, 2-5% for lidocaine, diltiazem and verapamil, and 1.2 and 2.4% for the two pindolol enantiomers. Recoveries, limits of detection and linearities are provided.