A simple and fast method to fabricate nanostructured substrates with silver nanoparticles over a large area for surface-enhanced Raman scattering (SERS) is reported. The method involves two steps: (1) dip the substrate into a silver nitrate solution for a few minutes, remove the substrate from the solution, and then air dry and (2) process the silver nitrate coated substrate by femtosecond (fs) laser pulses in air. The second step can create silver nanoparticles distributed on the nanostructured surface of the substrate by the photoreduction of fs multiphoton effects. This study demonstrates that an enhancement factor (EF) greater than 5×10⁵, measured by 10ˉ⁶ M Rhodamine 6G solution, can be achieved. The proposed technique can be used to integrate the SERS capability into a microchip for biomedical and chemical analysis. © 2010 Springer-Verlag.