Simultaneous ion counting and waveform averaging implemented on a field-programmable gate array compiled with a high-speed digitizer was applied to ultraperformance liquid chromatography-time-of-flight mass spectrometric analysis of sulfa drugs. Ion counting was carried out by a "Peak Detection" (PKD) function that works together with signal averaging (AVG). Sulfadimidine (SDD) and sulfadimethoxine (SDMX) were measured in human serum (HS) model sample matrix. By using simultaneous PKD and AVG acquisition, we observed a unified calibration curve for more than 3 orders of magnitude of sample amounts (0.010-100.0 pmol). The ion count rate for the "practical" sample amounts, such as less than 1 pmol, was below 30%, which is suitable for PKD-based ion counting for quantitative accuracy and excellent peak identification performance. Samples containing 200 fmol or less could not be identified from the AVG waveform. Adding HS treated with acetonitrile severely suppressed the SDMX ion to less than one-half (58.1%). However, a linear response was observed for chromatographic peak area for analytes calculated from PKD waveforms. Also, the mass-resolving power calculated from the peak on the PKD waveform was 24% better than the corresponding AVG waveform, which also improves performance for analyte identification.