Cardiopulmonary exercise testing (CPX) might aid in the diagnosis of coronary artery disease. However, a heterogeneous clinical population without previous workup bias has not been studied nor has a more extensive list of CPX variables. A total of 303 subjects (age 49.9 ± 11.6 years, 157 men) with symptoms suggestive of coronary artery disease underwent CPX and a single photon emission computed tomographic myocardial perfusion study (MPS). Ventilatory efficiency was calculated using the oxygen uptake efficiency slope (OUES). The change in the OUES was calculated by subtracting the OUES response during the first 50% of CPX from the OUES obtained during the last 25% of CPX. A negative change in the OUES (<0) from the first 50% to the last 25% of CPX was predictive of positive MPS findings only in the male subjects. The diagnostic significance of the change in OUES in men was found for any level (including equivocal studies) of positive MPS findings (area under the curve 0.67, 95% confidence interval 0.59 to 0.76, p <0.0001) and was even stronger in those with a more definitive (excluding equivocal studies) perfusion defect (area under the curve 0.76, 95% confidence interval 0.67 to 0.85; relative risk 5.4, 95% confidence interval 2.1 to 13.8, p <0.0001). In conclusion, this is the first time that a change in ventilatory efficiency, assessed using the OUES, has been shown to be predictive of positive MPS findings However, the OUES change only provided diagnostic information for men, a finding that warrants additional analysis.