Key pointsr The oxygen cost of breathing represents a significant fraction of total oxygen uptake during intense exercise.r At a given ventilation, women have a greater work of breathing compared with men, and because work is linearly related to oxygen uptake we hypothesized that their oxygen cost of breathing would also be greater.r For a given ventilation, women had a greater absolute oxygen cost of breathing, and this represented a greater fraction of total oxygen uptake.r Regardless of sex, those who developed expiratory flow limitation had a greater oxygen cost of breathing at maximal exercise.r The greater oxygen cost of breathing in women indicates that a greater fraction of total oxygen uptake (and possibly cardiac output) is directed to the respiratory muscles, which may influence blood flow distribution during exercise.Abstract We compared the oxygen cost of breathing (V O 2 RM ) in healthy men and women over a wide range of exercise ventilations (V E ). Eighteen subjects (nine women) completed 4 days of testing. First, a step-wise maximal cycle exercise test was completed for the assessment of spontaneous breathing patterns. Next, subjects were familiarized with the voluntary hyperpnoea protocol used to estimateV O 2 RM . During the final two visits, subjects mimicked multiple times (four to six) the breathing patterns associated with five or six different exercise stages. Each trial lasted 5 min, and on-line pressure-volume and flow-volume loops were superimposed on target loops obtained during exercise to replicate the work of breathing accurately. At ß55 l min −1 V E ,V O 2 RM was significantly greater in women. At maximal ventilation, the absoluteV O 2 RM was not different (P > 0.05) between the sexes, but represented a significantly greater fraction of whole-bodyV O 2 in women (13.8 ± 1.5 vs. 9.4 ± 1.1%V O 2 ). During heavy exercise at 92 and 100% V O 2 max , the unit cost ofV E was +0.7 and +1.1 ml O 2 l −1 greater in women (P < 0.05). AtV O 2 max , men and women who developed expiratory flow limitation had a significantly greaterV O 2 RM than those who did not (435 ± 44 vs. 331 ± 30 ml O 2 min −1 ). In conclusion, women have a greateṙ V O 2 RM for a givenV E , and this represents a greater fraction of whole-bodyV O 2 . The greaterV O 2 RM in women may have implications for the integrated physiological response to exercise. Abbreviations EFL, expiratory flow limitation; MEFV, maximal expiratory flow-volume;V E , expired minute ventilation;V Emax , maximal expired minute ventilation;V O2 , oxygen uptake;V O2 max , maximal oxygen uptake;V O2RM , oxygen uptake of the respiratory muscles; WOB, work of breathing.