An HPLC methodology is described which enables the quantitation of thiothixene (N,N-dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidene]thioxanthe ne-2- sulfonamide) in bulk drug, finished product, and dissolution samples using a single analytical column (SiAl: a mixture of silica and alumina). The Z (cis) and the less pharmacologically active E (trans) isomers of thiothixene, as well as synthetic precursors and degradants, are well resolved within a short chromatographic run. A minor modification of the mobile phase allows direct injection and quantitation of low-concentration samples in a simulated gastric fluid (SGF) dissolution medium. The method is capable of supplanting the three separate procedures currently included in the thiothixene monograph of the U.S. Pharmacopeia XXI.