The ventilatory response to changes in alveolar (arterial) CO2 is widely used as an index of respiratory control behavior. Methods for estimating these response slopes should incorporate the possibility that there may be errors in both the independent (partial pressure of CO2) and dependent (ventilation) variables. In a recent paper Daubenspeck and Ogden (J. Appl. Physiol. Respirat. Environ. Exercise Physiol. 45:823–829, 1978) have suggested problems inherent in the traditional technique of reduced major axis and have suggested a more contemporary technique of directional statistics. We have previously analyzed both techniques and developed a method to overcome the problems of reduced major axis and problems inherent in the use of directional statistics. Under the assumption of a bivariate normal distribution, we demonstrate that our slope estimate is similar to the maximum likelihood estimate proposed by Mardia et al. (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 54: 309–313, 1983) for this problem. In addition, we demonstrate a bootstrap statistical approach when the distributions are not normally distributed. These concepts are illustrated using O2-CO2 interaction data.