The high demands of manual wheelchair propulsion put users at risk of additional pain and injury that can lead to further reductions in independence and quality of life. Seat position is an adjustable parameter that has been shown to influence propulsion biomechanics. As a result, a number of studies have attempted to optimize this position. However, due to complexities in quantifying upper extremity demand, seat position guidelines are often based on studies aimed at reducing indirect quantities (e.g., cadence, handrim forces, joint ranges of motion and muscle excitation levels) rather than more direct measures of demand (e.g., muscle stress and metabolic cost). Forward dynamics simulations provide an alternative approach to systematically investigate the influence of seat position on more direct measures of upper extremity demand. The objective of this study was to generate and analyze a set of forward dynamics simulations of wheelchair propulsion across the range of attainable seat positions to identify the optimal seat position that minimizes upper extremity demand (i.e., muscle stress, metabolic cost and muscle antagonism). The optimization results showed both metabolic cost and muscle stresses were near minimal values at superior/inferior positions corresponding to top dead center elbow angles between 110 and 120 degrees while at an anterior/posterior position with a hub-shoulder angle between -10 and -2.5 degrees. These minimal values coincided with a reduction in the level of antagonistic muscle activity, primarily at the glenohumeral joint. Seat positions that deviated from these minimal values increased the level of co-contraction required to maintain a stable, smooth propulsive stroke, and consequentially increased upper extremity demand. These results can provide guidelines for positioning the seat to help reduce upper extremity overuse injuries and pain, and thus improve the overall quality of life for wheelchair users.