I. INTRODUCTION 2 Earlier studies on the SERS spectrum of lysozyme molecules adsorbed on Ag electrodes and hydrosols indicate the proximity of the S-S bond and aromatic amino acid residues of Lysozyme is a small monomeric globular protein consisting of 129 amino acids that has the ability to disrupt many bacterial functions including their membrane structure [11–14]. The protein has α -helix and β -sheet components with four disulfide bonds. It contains six tryptophan (Trp) residues, three of them are located at the substrate binding sites, two in the hydrophobic matrix box, while one is separated from the others [15]. Among them Trp 62 and Trp108 are the most dominant fluorophores, both being located at the substrate binding sites [16]. Lysozyme action on bacteria has been the focus of a lot of research, but interaction studies with Ag colloids have not previously revealed the specific interaction sites on the protein. We have further probed the interactions of lysozyme with Ag nanoparticles to obtain an insight into the specific residues involved in the interaction. This has been investigated by spectral methods and new insights have been obtained in the understanding of how this protein is involved in the interaction with Ag colloids. Metal nanoparticles are finding increasing use in nanomedicine for surface interactions with an array of proteins and/or small molecules. Metal nanoparticles tagged to biomacro- molecules are oftentimes used to identify specific antibody-antigen binding sites in cells and tissues [1, 2]. Surface Enhanced Raman scattering (SERS) is an extremely sensitive technique for monitoring the adsorption of species of very low concentration and for char- acterizing the structure and orientation of the adsorbed species on the rough metal surface or metal colloidal particles [3]. Nonresonance SERS is primarily sensitive to the species at- tached to the metal surface or present within a few of the metal-dielectric interface as well as to the orientation of the ad-molecule [4]. Thus, it is possible to characterize molecular rearrangement on the metal surface by SERS mechanism. This implies that conformational changes occurring in the protein structure or due to denaturation through possible interac- tions with metal particles can be detected from a detailed analysis of the SERS spectrum. Modification of the specific interaction sites by covalent or non-covalent methods makes the possibilities of study enormous. In this regard, the interactions of silver nanoparticles with several proteins have been investigated. Some of the proteins studied with silver (Ag) colloids are hemoglobin [5], antirabbit IgG [6], albumin [7] and lysozyme [8–10].