The fabrication of line-like periodic structures on poly-hydroxyethyl-methacrylate (PHEMA) polymers used as soft contact lenses was studied by using direct laser interference patterning. As the laser source, a mode-locked solid-state oscillator delivering 12 ps laser pulses at a central wavelength of 355 nm was used to structure the surface of the samples. Laser parameters in terms of laser fluence, spatial period, and pulse-to-pulse overlapping were modified to determine the optimal conditions for the polymer to be structured. Optical confocal microscopy and micro-Raman spectroscopy were used to evaluate the topography and the microstructural changes induced in the processed samples. Also, diffraction assessment was carried out under illumination of a continuous-wave 632.8 nm He-Ne laser in the DLIP processed areas to determine the refractive index change variation achieved in the structured areas. Finally, static water contact angle (WCA) measurements were performed with deionized water droplets on the structured areas to investigate the hydration properties of DLIP structures.