Respirator inspiratory and expiratory breathing resistances impact ventilation and performance when studied independently. However, it is less clear as to how various combinations of inhalation and exhalation resistance affect user performance. The present study investigated the performance of 11 individuals during constant load, demanding work to exhaustion while wearing respirators with eight different combinations of inhalation and exhalation resistance. Exercise performance time, performance rating, minute volume, and peak inspiratory and expiratory airflow were recorded at the end of each test trial, and independent correlations with inhalation resistance and exhalation resistance were assessed. The combined impacts of respirator inhalation and exhalation resistances were quantified as the total external work of breathing (WOB(tot)) and correlations between the test variables and WOB(tot) were also examined. Significantly linear decreases in performance were found with increased inhalation resistances independent of exhalation resistance (R(2) = 0.99; p < 0.001) and with increased WOB(tot) (R(2) = 0.92; p < 0.001). Performance also decreased with increased exhalation resistance but no significant relationships were found. Minute volume decreased linearly with increased inhalation resistance independent of exhalation resistance (R(2) = 0.99; p < 0.001), but the linear decrease observed between minute volume and WOB(tot) was weak (R(2) = 0.36; p < 0.05). These findings suggest that WOB(tot) serves as a reliable estimate of the combined impacts of respirator inhalation and exhalation resistances on user performance during hard work, but that inhalation resistance alone serves as a better predictor of ventilation during respirator wear.