We demonstrate the realization of the first label-free optical biosensor based on the room temperature luminescence of silicon nanowires (NWs) tested for the selective detection of C-reactive protein in human serum. High aspect ratio Si NW arrays used as sensing interface, are synthesized by a fast, low cost and Si industrially compatible approach. Si NW optical biosensors are fast and offer a broad concentration dynamic range that can be tuned according to different applications. Moreover, the platform is endowed with a high selectivity toward the target analyte and a sensitivity down to the fM limit of detection, opening the route toward noninvasive analysis in biofluids such as saliva.