While it is generally recognized that anatomical differences exist between the male and female knee, the literature generally refutes the clinical need for gender-specific total knee prostheses. It has been found that standard, unisex knees perform as well, or better, in women than men. Recently, high-flex knees have become available that mechanically accommodate increased flexion yet no studies have directly compared the outcomes of these devices in men and women to see if gender-based differences exist. We retrospectively compared the performance of the high-flex Vanguard knee (Biomet, Warsaw, IN) in 716 male and 1,069 female knees. Kaplan-Meier survivorship was 98.5% at 5.6-5.7 years for both genders. After 2 years, mean improvements in Knee Society Knee and Function scores for men and women (50.9 versus 46.3; 26.5 versus 23.1) and corresponding SF-12 Mental and Physical scores (0.2 versus 2.2; 13.7 versus 12.2) were similar with differences not clinically relevant. Postoperative motion gains as a function of preoperative motion level were virtually identical in men and women. This further confirms the suitability of unisex total knee prostheses for both men and women.