This study determined the time course of changes in resting and exercising respiratory responses during the first half of human pregnancy, and examined the potential roles of plasma osmolality and the strong ion difference ([SID]) as mediators of pregnancy-induced increases in ventilation. Healthy active women (n = 11) were studied serially from 7 to 22 weeks gestation. Responses were compared with preconception data from 14 subjects (six of whom were tested in early pregnancy), and with late-gestation resting data from 10 additional women. Resting and exercising measurements included ventilation, PaCO2, progesterone, osmolality and [SID]. Results were analyzed using mixed-model linear regression. By 7 weeks gestation, increased ventilation resulted in a very large decrease in PaCO2 at rest and during moderate-intensity exercise. Large correlations (r > 0.5) between resting progesterone and PaCO2 support the traditional theory that circulating progesterone stimulates ventilation during pregnancy. The similar time course of changes and large correlations between raw and delta values of PaCO2 and each of plasma osmolality and [SID] also suggest that both variables may influence respiratory control at rest and during exercise in the first half of pregnancy. Future experiments should continue to explore the hypothesis that osmolality and [SID] contribute to pregnancy-induced respiratory changes.