The vicinity of metallic nanostructures that provides intense optical fields is termed as “hot spot”. Any molecule in close proximity to these hot spots will give rise to an increased surface-enhanced Raman spectroscopic (SERS) signal. We have synthesized Ag core−Au shell (core−shell) nanoparticles (NP) with nanopores, which act as hot spots in the SERS measurements. We have demonstrated a large enhancement in SERS studies of various molecules using core−shell NP with hot spots, which is better than using silver nanoparticles. The core−shell NP with hot spots can be used for ultratrace analysis of important biomolecules such as histone acetyltranferase p300, a human transcriptional coactivator protein. The core−shell NP does not change the biomolecule's physical and chemical property upon adsorption, which makes it biocompatible. The core−shell NP carrying hot spots with high SERS enhancement would be ideally suited for in vivo studies of biological systems.