Objective The effect of menopause on breathing is not fully understood. We have previously shown that postmenopausal women have a higher sleep-induced increase in transcutaneously measured carbon dioxide tension (TcCO₂) than premenopausal women. Therefore, we hypothesized that estrogen therapy (ET) would normalize this sleep-induced TcCO₂ increase. Methods Nine postmenopausal ET users and nine non-users went through an overnight polygraphic sleep study including continuous monitoring of TcCO₂. Results TcCO₂ levels were higher during sleep than evening wakefulness (awake median 6.55 kPa versus sleep median 6.90 kPa, P = 0.001). ET users had a greater sleep-induced increase in TcCO₂ than non-users when comparing the difference between wakefulness and slow-wave sleep (0.85 kPa versus 0.28 kPa, P = 0.004). Lower sleep efficiency was associated with higher sleep-induced increase in TcCO₂. Conclusions In contrast to our initial hypothesis, postmenopausal ET users have a higher sleep-induced increase in TcCO₂ than women without ET. Thus, TcCO₂ may be sensitive in measuring the peripheral estrogen effect. These findings warrant placebo-controlled intervention studies to confirm the effects of ET on TcCO₂ measurements.