The separation of basic pharmaceuticals is usually performed on C8 or C18 bonded silica supports. Silanolphilic interactions between basic analytes and surface silanol groups often lead to tailed peaks, poor efficiency, and irreproducible retention times. To solve these problems, many new types of silica-, zirconia-, and polymer-based columns, which provide unique selectivities, improved stability at high pH, or both, have been developed for the analysis of basic compounds. The essence of method development for the chromatographic analysis of basic compounds is to choose a system in which the band spacing can be varied dramatically, quickly, and conveniently while minimizing the tailing due to silanolphilic interactions. The thermally tuned tandem column (T3C) approach has been shown to provide an effective way to adjust stationary-phase selectivity for nonionic compounds. In this study, a tandem combination of an octadecylsilane (ODS) and a polybutadiene-coated zirconia (PBD-ZrO2) phase was used to separate nine antihistamines. Selectivity is tuned by independently adjusting the isothermal temperatures of the two columns. We found dramatic differences in the retention factors, elution sequences, and band spacing for the above set of basic drugs on the two types of columns. The T3C model has been used successfully to locate the optimal temperatures based on only four exploratory runs. The nine antihistamines were baseline separated on the tandem column combination even though they could not be separated on the individual phases. The effect of the buffer concentration on retention of the basic antihistamines was also studied. We conclude that cation-exchange interactions predominate on the PBD-ZrO2 phase, while reversed-phase interactions are more important on the ODS phase. Interestingly, an increase in column temperature causes a significant increase in the retention on the ODS column and a decrease of retention on the PBD-ZrO2 column. This can be explained by the change in the analyte's degree of ionization with temperature. The T3C combination of silica- and zirconia-based RPLC columns is demonstrated to be a powerful approach for the separation of this mixture of basic analytes.