Abstract Purpose Dry Eye Syndrome (DES) is an ocular surface disease with higher prevalence in women than in men. It is characterized by decreased tear gland secretion, altered tear composition and tear film instability. We investigated whether supplementation with the isoflavone genistein (GEN) could alleviate artificially induced DES in rats. Methods DES was induced in 24 female Sprague Dawley rats by daily trans‐dermal treatment with scopolamine (SCOP). Animals were housed on an AIN feed containing 0, 50 or 250 ppm of GEN provided as geniVida® by DSM Nutritional Products. 8 additional animals served as not‐stressed control. After 2 and 4 weeks, levels of GEN in plasma were measured by LC/MS and the status of DES was assessed using the Zone Quick Test (ZQT). After 4 weeks, animals were sacrificed and cornea and conjunctiva were examined for Goblet Cell Density (GCD) and the extent of lid keratinization (LK). Pairwise comparisons of endpoint values were done by t‐test or Mann‐Whitney test. Results Genistein feeding resulted in significant increases of plasma genistein concentrations. The achieved levels were commensurate to those reported in a human study supplementing 60 mg/day (Ullmann et al. (2005), Planta Med. 71: 891‐896), equivalent to 100g soy beans per day. In the 0 ppm GEN group, SCOP treatment increased the extent of LK and drastically reduced ZQT and GCD values, while genistein supplementation restored tear volume (p=0.0007), GCD (p=0.0028) and LK (p=0.0009) in a dose‐dependent manner. Conclusion While these results still need to be confirmed in humans, genistein supplementation may become a treatment option that fundamentally restores natural tear physiology, offering a major improvement over the currently used topical agents. Commercial interest