We have synthesized a biocompatible polyaspartic acid-based polymer (molecular weight similar to 15 000-25 000) with cysteine on its backbone for use as a capping ligand for functionalized Au, Ag, and CdSe@ZnS nanoparticles. Nearly monodisperse, hydrophobic Au and Ag nanoparticles and CdSe@ZnS quantum dots were first prepared in organic solvents via conventional synthesis and then ligand exchanged to derive polymer-coated water-soluble nanoparticles. Multiple thiol groups in the polymer backbone conferred excellent protection against aggregation of the nanoparticles, and the carboxylic acid groups in the polymer provided the possibility of covalent binding with antibodies. Compared to the conventional thiol-based ligands, this polymer coating led to superior colloidal stability under the experimental conditions involved in the bioconjugation and purification steps. Goat antihuman-IgG (anti-h-IgG) and antimouse epidermal growth factor receptor (anti-m-EGFR) antibodies were conjugated with the polymer-coated nanoparticles and successfully applied to protein detection. This polymer coating exhibited minimal nonspecific interaction with cells and could be broadly applied to cell labeling.