Introduction Glycated hemoglobin can interfere with oxygen delivery and CO 2 removal during exercise. Additionally, pancreatic insufficiency increases oxidative stress and exacerbates exercise intolerance in people with cystic fibrosis (PwCF). This investigation sought to test the hypotheses that elevated Hemoglobin A 1c (HbA 1c ) can negatively affect exercise parameters in PwCF and that reductions in oxidative stress can improve tissue oxygenation in individuals with elevated HbA 1c . Methods Twenty four PwCF were divided into two groups; normal HbA1c textless5.7% (N-HbA 1c ) and elevated HbA 1c textgreater5.7% (E-HbA 1c ). A maximal exercise test was conducted to obtain peak oxygen uptake (VO 2 peak), VO 2 at ventilatory threshold (VT), ventilatory parameters (V E /VCO 2 slope and end-tidal CO 2 (petCO 2 )). Near-Infrared Spectroscopy (NIRS) was used to assess muscle oxygenated/deoxygenated hemoglobin during exercise. A subset of individuals with E-HbA 1c were given an antioxidant cocktail (AOC) for 4 weeks to determine the effects on tissue oxygenation during exercise. Results A negative relationship between HbA 1c and VO 2 peak at VT was observed (r = −0.511; p = 0.018). In addition, a positive relationship between HbA 1c and V E /VCO 2 slope ( r = 0.587; p = 0.005) and a negative relationship between HbA 1c and petCO 2 at maximal exercise ( r = −0.472 ;p = 0.031) was observed. N-HbA 1c had greater VO 2 peak ( p = 0.021), VO 2 at VT ( p = 0.004), petCO 2 ( p = 0.002), and lower V E /VCO 2 slope ( p = 0.004) compared with E-HbA 1c . Muscle deoxygenated hemoglobin at VT was higher in N-HbA 1c vs. E-HbA 1c and 4 weeks of AOC improved skeletal muscle utilization of oxygen. Conclusion Findings demonstrate that glycated hemoglobin may lead to tissue oxygenation impairment and ventilation inefficiency during exercise in PwCF. In addition, antioxidant supplementation may lead to improved tissue oxygenation during exercise.