This paper reports oil the use of silicon nanowires (SiNWs), easily prepared in a single step by chemical etching of crystalline silicon in HF/AgNO3 aqueous solution, as a highly sensitive substrate for laser desorption/ionization mass spectrometry (LDI-MS) analysis. The SiNWs' diameter and length depend oil the etchant concentration and dissolution time. Optimized LDI substrate consists of nanowires with an average diameter in the range of 20-100 nm and 2.5 mu m in length. The optimized SiNWs' surface morphology Coupled to a controlled surface chemistry allowed a significant LDI-MS performance through measurements of a broad range of analytes, including small molecules, peptides, and a bovine serum albumin (BSA) digest. A signal-to-noise ratio of 250 was ascertained for a 10 fmol bradykinin pick, in reflector mode acquisition. Likewise, the sutent, a small tyrosine kinase inhibitor, could be observed down to 10 fmol, as compared to 500 fmol limit detection using the classical matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS). We have further investigated the optical properties of the nanowires, and our results Suggest that they have a small or no effect oil the desorption/ionization (D/I) process. On the contrary, the surface morphology and thermal properties of the silicon nanostructures are found to be the essential features contributing to the D/I performance.