Ultra-performance liquid chromatography (UPLC) was investigated as an alternative to high-performance liquid chromatography (HPLC) for analyzing pharmaceutical drug candidates. We previously developed a 96-well-based high-speed solubility assay system (HSSOL) using HPLC/UV and a LogD assay system (HSLogD) using HPLC/MS [Y. Dohta, T. Yamashita, S. Horiike, T. Nakamura, T. Fukami, Anal. Chem. 79 (2007) 8312]. We have introduced the UPLC/MS system into this previously developed HSSOL system to increase throughput. Results obtained by the UPLC/MS and HPLC/UV systems showed good agreement, validating the usefulness of the UPLC/MS system. A high-speed solubility assay system was developed employing the UPLC/MS system, thereby tripling the throughput.