In this study, the potential application of surface-enhanced resonance Raman scattering (SERRS) spectroscopy as an off-line secondary detector for HPLC has been evaluated. Four nitrophenol compounds, 2-nitrophenol, 4-nitrophenol, 2,4-dinitrophenol, and 4,6-dinitrocresol were separated by isocratic reverse-phase high-performance liquid chromatography (RP-HPLC) and monitored with a conventional UV detector. Resonance Raman (RR) and SERRS spectroscopy were next used to provide the required specificity for distinguishing the nitrophenol compounds. The SERRS detection limit for both 2-nitrophenol and 4-nitrophenol was calculated to be 14 ppb and that for 2,4-dinitrophenol and 4,6-dinitrocresol was estimated to lie near the parts-per-billion level as well. This detection limit is 2-3 orders of magnitude lower than that obtained by RR spectroscopy.