Resting oxygen consumption (VO2) and minute ventilation (VE) were measured on nine control subjects and 13 patients with cystic fibrosis (CF). In patients with CF, VO2 was 20% higher (P less than 0.01) when expressed per m2 and 47% higher (P less than 0.001) when expressed per kg body weight, and VE was 58% higher when expressed per m2 and 94% higher when expressed per kg body weight (P less than 0.001) than in control subjects. Repeated measures of VO2 and VE were highly reproducible over 2 hours (within-subject coefficients of variation: in controls, VO2 = 5.5%, VE = 7.4%; in CF, VO2 = 3.1%, VE = 5.1%). Since the increases in VE were greater than those in VO2, the ventilatory equivalent (VE/VO2) was 32% higher in CF than in controls. We conclude that size-corrected total energy expenditures and VE at rest are higher in patients with CF than in control subjects. Ventilation appears mechanically inefficient but necessary to keep arterial PCO2 from rising and oxygen saturation from falling at rest. Our results are consistent with observations that these patients have an abnormally large physiological dead space (Featherby et al.: Ann Rev Respir Dis 1969; 102:737).