The prevalence of activity-related breathlessness increases with age, particularly in females, but the specific underlying mechanisms have not been studied. This cross-sectional study was undertaken to examine the effects of age, gender and their interaction on the perceptual and ventilatory responses to incremental treadmill exercise in 73 healthy participants (age range 40-80 years) with normal pulmonary function. Age-related changes at a standardized oxygen uptake (V'O₂) during exercise included: significant increases in breathlessness ratings (Borg scale), ventilation (V'_E), ventilatory equivalent for carbon dioxide and the ratio of tidal volume (V_T) to dynamic inspiratory capacity (IC) (all p<0.05). These changes were quantitatively similar in females (n=39) and in males (n=34). For the group as a whole, exertional breathlessness ratings increased as resting static inspiratory muscle strength diminished (p=0.05), as exercise ventilation increased relative to capacity (p=0.013) and as the V_T/IC ratio increased (p=0.003) during exercise. Older females (60-80 years, n=23) reported greater (p<0.05) intensity of exertional breathlessness at a standardized V'O₂ and V'_E than age-matched males (n=16), despite similar age-related changes in ventilatory demand and dynamic ventilatory mechanics. These increases in breathlessness ratings in older females disappeared when gender-differences in baseline maximal ventilatory capacity were accounted for. Conclusion: Although increased exertional breathlessness with advancing age is multifactorial, contributory factors included: higher ventilatory requirements during exercise, progressive inspiratory muscle weakness and restrictive mechanical constraints on V_T expansion related to reduced IC. The sensory consequences of this age-related respiratory impairment were more pronounced in females who, by nature, have relatively reduced maximal ventilatory reserve.