The effect of X-ray irradiation on the chemical and physical properties of a semifluorinated self-assembled monolayer (CF-SAM) derived from 1H,1H,2H,2H-perfluorodecanethiol (CF3(CF2)(7)(CH2)(2)SH) adsorbed on gold and copper substrates was studied using X-ray photoelectron spectroscopy. During the initial period of irradiation, the effects of electron-stimulated C-F, C-C, and S-X (X = Au, Cu) bond breaking are responsible for changes in the chemical composition of the CF-SAM. Furthermore, the evolution of the C(Is) X-ray photoelectron spectral region indicates that C-F rather than C-C bond cleavage dominates desorption within the CF-SAM. Except for fluorine desorption, irradiation-induced changes to the chemical and structural properties of the CF-SAM were most pronounced during the initial stages of irradiation, prior to the development of a highly cross-linked carbonaceous overlayer. X-ray irradiation of CF-SAMs adsorbed on An also resulted in the production of new irradiation-induced sulfur species. A comparison with experiments carried out on a n-hexanedecanethiol (CH3(CH2)(15)SH)-based SAM revealed that the concentration and distribution of these irradiation-induced sulfur species were both sensitive to the SAM's initial chemical composition. On Cu substrates, native CF-SAMs formed an effective barrier to oxygen diffusion although the film's permeability to oxygen increased for CF-SAMs pre-exposed to X-ray irradiation.