5-Fluorouracil, an extensively used anticarcinogenic drug, was found to undergo a soft adsorption (i.e., no significant structural changes) on the metal surface of different Ag island films (35, 11, 8.7, and 6.5 nm thick). The 35 nm thick film provided the best SERS signal. The resistance of the Ag-complexed species to washing demonstrates the films' advantage over colloids and makes them very attractive for potential bio-applications. Both deprotonated forms, which were previously detected on colloidal nanoparticles (50 nm diameter) at neutral pH, are also present in this case. However, the interaction mechanism of 5-FU species appears to be substrate dependent. While on colloidal nanoparticles they are orientated perpendicular or significantly tilted from the surface normal, on the much larger Ag-clusters of the island films (20-200 nm) they lie flat, attached through the carbonyl groups and the pi-electrons. The charge-transfer mechanism significantly contributes to the rich information SERS reports for this system.