1,1,5,5-Tetramethylcarbohydrazide (TMCH) is the main precursor of N-nitrosodimethylamine upon ozonation in the Yodo River basin, Japan. This study was performed to develop an analytical method for TMCH using solid-phase extraction with ultra-high performance liquid chromatography–tandem mass spectrometry. TMCH is hydrophilic and a tertiary amine derivative, so Oasis^® MCX cartridges were used as solid-phase cartridges. The recoveries of TMCH in tap and river waters as well as secondary effluent from a sewage treatment plant ranged from 75 to 94%. The limit of quantification of TMCH was 4 ng L⁻¹. The source of TMCH in the Yodo River basin was found to be effluent from one sewage treatment plant. The concentrations were < 4 ng L⁻¹ in raw water from water purification plants in regions other than the Yodo River basin, indicating that TMCH was used specifically in the basin.