The purpose of this study was to identify optimal ways to detect neurogenic changes with high-density surface electromyography (HD-sEMG). For this purpose, we searched for the variables that most clearly discriminated between postpoliomyelitis and healthy subjects. We obtained HD-sEMG from the quadriceps muscle at different force levels in nine subjects with postpoliomyelitis syndrome and in matched healthy controls. Single motor unit action potentials (MUAPs), extracted from the HD-sEMG signal and the raw signal itself, were analyzed. Areas under the curve of the extracted MUAP waveform, indicating motor unit size, perfectly separated both groups. Raw signal analysis showed significant differences between groups for the monopolarly recorded amplitude up to 60% of maximal force and for the level of interference at higher force levels (40-100% force). We conclude that with HD-sEMG it is possible to detect neurogenic motor unit changes noninvasively, both by analysis of the raw signal itself and by analysis of extracted single MUAPs. The diagnostic yield of the single MUAP analysis is clearly higher. These findings point toward applications for clinical practice and invite further studies exploring the diagnostic value of HD-sEMG.