We have employed the proposed Silica-Silver Core-Shell (SSCS) SERS-active substrates to detect four model proteins: lysozyme (a protein without chromophore), cytochrome c (a protein with chromophore of heme), fluorescein isothiocyanate (FITC)-anti human IgG (labeled with FITC) and atto610-biotin/avidin (recognition with labeled small molecules). SERS spectra of these proteins and Raman labels on the SSCS substrates show both high sensitivity and reproducibility, which are due to electromagnetic SERS enhancement with additional localization field within closely packed Ag nanoparticles decorated on the SiO(2) nanoparticles and the aggregation of SiO(2)@Ag particles. We have found that the SERS intensities of atto610-biotin/avidin adsorbed on the SSCS substrates are about 20 times stronger than those from Ag plating on Au-decorated substrate. Moreover, the broad surface plasmon resonance (SPR) of the proposed substrates will extend SERS applications to more biological molecules with different laser excitations. (C) 2011 Elsevier Inc. All rights reserved.