Abstract: A simple, rapid and specific method for optimization of mobile phase selectivity used in reversed-phase high performance liquid chromatography (RP-HPLC) was described. The new method of optimization called orthogonal design-simplex method has combined orthogonal design concept with modified sequential simplex algorithm. When four factorial simplex is used with the help of a microcomputer, the vertices of the initial simplex can be calculated by orthogonal design. Tests using solvent mixtures with five ingredients contained in compound anti-hypertensive tablets (including vitamin B₆, vitamin B₁, nepresol and hydrochlorothiazide, and a decomposed product of hydrochlorothiazide) have clearly demonstrated the advantages of the orthogonal design-simplex method over other chromatographic optimization techniques.