OBJECTIVE To validate a noninvasive first-pass radionuclide ventriculographic (FPRV) measurement of maximum cardiac output (Qv) during exercise. METHODS Comparison of Qv to that measured by the Fick principle (Qf) at peak exercise. METHODS Academic cardiopulmonary exercise laboratory. METHODS Seventy-eight consecutive patients without a history of septal defect undergoing clinically indicated maximum incremental cardiopulmonary exercise testing with pulmonary arterial catheterization and FPRV. RESULTS Ventilation and gas exchange were measured breath-by-breath or by a mixing chamber/mass spectrometer system. Arterial and mixed venous O2 content were measured each minute during exercise. When patients without left-to-right ventricular stroke count ratio evidence for left-sided regurgitation were isolated, peak Qv was linearly related to Qf (r=0.75, p=0.0001). To account for a small systematic overestimation (bias) of Qf by Qv, the linear equation for the Qv/Qf relation was derived for patients studied between 1990 and 1993 and applied to those studied subsequently. The resulting corrected peak Qv was tightly related to peak Qf (r=0.90, p<0.001) with confidence intervals for slope and intercept overlapping identity. CONCLUSIONS FPRV can reasonably estimate maximum cardiac output during incremental exercise in patients for whom the technique has ruled out left-sided cardiac regurgitant lesions.