Sweat Na(+) concentration ([Na(+)]) varies greatly among individuals and is particularly high in cystic fibrosis (CF). The purpose of this study was to determine whether excess sweat [Na(+)] differentially impacts thirst drive and other physiological responses during progressive dehydration via exercise in the heat. Healthy subjects with high-sweat [Na(+)] (SS) (91.0 ± 17.3 mmol/l), Controls with average sweat [Na(+)] (43.7 ± 9.9 mmol/l), and physically active CF patients with very high sweat [Na(+)] (132.6 ± 6.4 mmol/l) cycled in the heat without drinking until 3% dehydration. Serum osmolality increased less (P < 0.05) in CF (6.1 ± 4.3 mosmol/kgH(2)O) and SS (8.4 ± 3.0 mosmol/kgH(2)O) compared with Control (14.8 ± 3.5 mosmol/kgH(2)O). Relative change in plasma volume was greater (P < 0.05) in CF (-19.3 ± 4.5%) and SS (-18.8 ± 3.1%) compared with Control (-14.3 ± 2.3%). Thirst during exercise and changes in plasma levels of vasopressin, angiotensin II, and aldosterone relative to percent dehydration were not different among groups. However, ad libitum fluid replacement was 40% less, and serum NaCl concentration was lower for CF compared with SS and Control during recovery. Despite large variability in sweat electrolyte loss, thirst appears to be appropriately maintained during exercise in the heat as a linear function of dehydration, with relative contributions from hyperosmotic and hypovolemic stimuli dependent upon the magnitude of salt lost in sweat. CF exhibit lower ad libitum fluid restoration following dehydration, which may reflect physiological cues directed at preservation of salt balance over volume restoration.