This methodological paper presents a novel approach to predict operator's mechanical exposure and fatigue accumulation in discrete event simulations. A biomechanical model of work-cycle loading is combined with a discrete event simulation model which provides work cycle patterns over the shift resulting in a load-time trace for the entire shift. This trace was tested with four different muscle endurance-recovery model pairs yielding a fatigue-time history for the entire shift. An electronics assembly case with shift-long perceived fatigue data was compared to the simulation model results. Sensitivity testing of the input work-rest ratios found the best correlation (r2=0.84) at 17% of the modeled rest level. The need for this adjustment is discussed in terms of limitations of available muscle endurance and recovery models. Muscle model limitations notwithstanding, this approach allows system designers to understand the mechanical exposure and fatigue-related effects of proposed alternatives in system design stages and can contribute to 'Virtual Human Factors' approaches for pro-active ergonomics capability. Relevance to Industry: This paper demonstrates an approach to quantifying operator exposure patterns and fatigue levels using dynamic simulations of the proposed operations. This allows system designers to understand the ergonomic impacts of proposed alternatives in system design. Design level tools allow early stage application of ergonomics where costs are lower and solution options are greatest. © 2013 Elsevier B.V.