Patients with cystic fibrosis (CF) desaturate during sleep and during exercise but by different mechanisms. To determine the need for supplemental oxygen, many centers measure resting and exercise arterial oxygen saturation (SaO2). We examined the associations among resting, sleep, and exercise SaO2 to ascertain the validity of this approach. We studied 21 adult and adolescent CF patients, eight of whom were hypoxemic (SaO2 less than 95 percent; group A) and 13 of whom were nonhypoxemic (SaO2 greater than or equal to 95 percent; group B) by overnight oximetry and treadmill exercise testing. The whole group desaturated more during sleep than during exercise, the change in SaO2 being 10.59 +/- 8.35 vs 6.25 +/- 4.44 (p less than 0.002). Group B desaturated significantly more during sleep than during exercise, with a reduction in SaO2 of 7.9 +/- 3.3 vs 3.3 +/- 1.49 (p less than 0.05). Group A desaturated more during exercise than group B, with a reduction of 11 +/- 3.2 vs 3.3 +/- 1.5 (p less than 0.001). Despite a strong correlation between awake SaO2 and mean sleep SaO2 (r = 0.68; p less than 0.001), minimum sleep SaO2 (r = 0.55; p less than 0.01), and minimum exercise SaO2 (r = 0.92; p less than 0.001), there was no correlation between awake SaO2 and sleep-related desaturation or between exercise- and sleep-related desaturation. In conclusion, clinically significant oxygen desaturation during sleep may be missed unless specifically checked in CF patients, and awake and exercise SaO2 may not give an indication of the degree of sleep-related desaturation.