Background context: Previous research has documented differences in spine loading between genders when the imposed load is normalized relative to the size of the person. However, under realistic work conditions the magnitude of the load handled is seldom adjusted relative to worker anthropometry. Thus, there is a void in our knowledge in that we do not understand how material handling influences spine loading and potential risk of injury as a function of gender under realistic lifting situations. Purpose: To evaluate the differences in spine loading between men and women when exposed to similar workplace demands. Study design: A laboratory study was conducted to investigate the biomechanical responses during realistic free-dynamic lifting tasks when subjects lifted from origins and destinations that were either fixed or set relative to the subject's anthropometry. Patient sample: Twenty men and 20 women asymptomatic for low back pain were recruited to participate in the study. Outcome measures: The three-dimensional spine loads were predicted from a well-established electromyography-assisted model. Methods: Both genders completed a series of symmetric and asymmetric (60-degree clockwise) lifts that originated from two shelf heights (“relative” to knee height and “set” at 35 cm from floor) and terminated at one of two destination heights (“relative” to waist and “set” 102 cm from the floor). Three levels of box weight were investigated (6.8, 13.6 and 22.7 kg). Results: Men had significantly greater compression forces than women (about 640 N). Loading differences between genders were further magnified by several of the workplace factors. The differences between men and women were even greater when lifting either of the heavier loads from the lower fixed shelf (more than 50% greater). Conclusions: It is apparent that men produce the greater loads on their spines during lifting. However, engineering controls, such as adjustable workplace layout or less weight lifted, may reduce or eliminate gender-specific differences in spine loads. Furthermore, the differences in spine loads appear to be a result of kinematic trade-offs and muscle coactivity differences in combination with unequal body masses between genders. However, when the loads were put into context of the expected tolerances of the spine, women were found to be at increased risk of injury, especially when lifting heavy loads or under asymmetric lifting conditions. Collectively, the results indicate the need to account for differences between the genders when designing the workplace.