Purpose: Cystic fibrosis (CF) is commonly recognized as a pulmonary disease associated with reduced airway function. Another primary symptom of CF is low exercise capacity where ventilation and gas-exchange are exacerbated. However, an independent link between pathophysiology of the pulmonary system and abnormal ventilatory and gas-exchange responses during cardiopulmonary exercise testing (CPET) has not been established in CF. Complicating this understanding, accumulating evidence suggests CF demonstrate abnormal peripheral vascular function; although, the clinical implications are unclear. We hypothesized that compared to controls, relative to total work performed (WorkTOT), CF would demonstrate increased ventilation accompanied by augmented systolic blood pressure (SBP) during CPET. Methods: 16 CF and 23 controls (age: 23-4 vs. 27-4 years, P = 0.11; FEV1%predicted: 73-14 vs. 96-5, P<0.01) participated in CPET. Breath-by-breath oxygen uptake (VO2), ventilation (VE), and carbon dioxide output (V CO2) were measured continuously during incremental 3-min stage step-wise cycle ergometry CPET. SBP was measured via manual sphygmomanometry. Linear regression was used to calculate VE=V CO2 slope from rest to peak-exercise. Results: Compared to controls, CF performed less WorkTOT during CPET (90-19 vs. 43-14 kJ, respectively, P<0.01).WithWorkTOT as a covariate, peak VE (62-8 vs. 90-4 L/min, P = 0.76), V CO2 (1.8-0.3 vs. 2.7-0.1 L/min, P = 0.40), and SBP (144-13 vs. 152-6 mmHg, P = 0.88) were similar between CF and controls, respectively; whereas CF demonstrated increased VE=V CO2 slope (38-4 vs. 28-2, P = 0.02) but lower peak VO2 versus controls (22 -5 vs. 33-4 mL/kg/min, P<0.01). There were modest-to-moderate correlations between peak SBP with VO2 (r = 0.30), VE (r = 0.70), and V CO2 (r = 0.62) in CF. Conclusions: These data suggest that relative to WorkTOT, young adults with mild-to-moderate severity CF demonstrate augmented VE=V CO2 slope accompanied by increased SBP during CPET. Although the underlying mechanisms remain unclear, the coupling of ventilatory inefficiency with increased blood pressure suggest important contributions from peripheral pathophysiology to low exercise capacity in CF.