Smaller airways increase resistance and the propensity toward turbulent airflow, both of which are thought to be mechanisms behind greater resistive and total work of breathing (Wb) in females. Previous research examining the effect of airway size on the Wb between the sexes is limited by the inability to experimentally manipulate airway size. Heliox (21% oxygen, balance helium) is less dense than room air, which reduces turbulent airflow and airway resistance. The purpose of our study was to utilize heliox inspiration in women to provide a stimulus physiologically similar to increasing airway size. We hypothesized that when breathing heliox women would have a Wb similar to men breathing room air. Eighteen healthy young subjects (n = 9 women, 9 men) completed two maximal exercise tests on a cycle ergometer over 2 days. Subjects breathed room air for one test and heliox for the other. Wb was assessed with an esophageal balloon catheter. During the room air trial, when ventilations were >65 L/min, women had a significantly greater Wb compared with men (P < 0.05). The greater Wb in women was due to greater resistance to turbulent flow. For both sexes, breathing heliox resulted in increased expiratory flow (+132 ± 18% of room air), an elimination of expiratory flow limitation, and a reduction in Wb (69 ± 12% of room air) (all P < 0.05). When the women were breathing heliox, Wb was not different from that in the men breathing room air. Our findings support the idea that the smaller conducting airways in females are responsible for a greater total and resistive Wb. NEW & NOTEWORTHY When healthy young women breathe heliox gas during exercise, their work of breathing is not different from men breathing room air. Heliox inspiration reduces airway resistance and promotes laminar flow, which is a physiologically similar effect of increasing airway size. Our findings provide experimental evidence that smaller airways in women are responsible for the greater work of breathing during exercise.