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We report a strong enhancement of two-photon fluorescence (TPF) excitation in the evanescent field of a double grating waveguide structure (DGWS). For a suitable combination of wavelength, polarization, and angular orientation of the incident laser light DGWSs show resonant behavior resulting in a large field enhancement at the waveguide surface. We demonstrate that at resonance, TPF spectroscopy reveals a 330-fold enhancement of the fluorescence signal of a tetramethylrhodamine thin film prepared from a picomolar aqueous solution. This shows the large potential of DGWSs as TPF-based high-sensitivity sensor platforms for biotechnological and biophysical application.