Chalcogenide electrocatalysts are very active and tolerant for the oxygen-reduction reaction (ORR) in electrolytes containing small organics. This property of tolerance allows them to be used as tolerant cathodes of direct methanol fuel cells (DMFC) that use highly concentrated methanol. Platinum chalcogenide-based cathodes of direct methanol fuel cells can overcome the problem of the formation of a mixed-potential due to the fuel crossover [Alonso-Vante et al., Patent-FR 12 55944, Appl. Filed 22 June 2012]. In this study, a comprehensive investigation on the origin of the tolerance of Pt chalcogenide electrocatalyst to small organic molecules such as methanol is provided. The XPS spectrum of Se 3d region in PtxSey/C revealed a shift of the selenium emission peak to lower binding energy as compared to a Se/C sample. This negative shift can be explained by charge transfer from the platinum surface atoms to the selenium, which is at the origin of the improved tolerance of Pt towards ORR in the presence of methanol. The physical chemical properties and electrochemical performances in half-cell and mixed-reactant microfluidic fuel cells are discussed.