Periodic breathing (PB) during exercise in patients with congestive heart failure (CHF) is associated with prominent oscillations (OSC) of O2 uptake (V̇O2). We hypothesized that the V̇O2 OSC in true O2 exchange, resulting from concomitant cardiac output fluctuations and are not merely due to OSC of lung O2 stores. We compared the amplitude of the OSC of V̇O2, ventilation (V̇E), and end-expiratory lung volume (EELV) in 17 patients with CHF and PB and in seven healthy control subjects who volitionally simulated PB. Subjects underwent an incremental and/or a constant work-rate exercise test. V̇E and V̇O2 were measured breath by breath. EELV change was estimated by summing the difference between inspiratory and expiratory tidal volumes for each breath. The amplitude of the OSC, Δ, is expressed as the ratio of the difference between the peak and nadir of the oscillating variable divided by its mean [Δ = (peak - nadir)/mean]. In CHF, during incremental testing, the amplitude of the V̇E OSC was smaller than that of the V̇O2 OSC (ΔV̇E = 49 ± 15% [SD], ΔV̇O2 = 63 ± 25%, p < 0.01). In contrast, during volitional PB in the control subjects, V̇E OSC were larger than V̇O2 OSC (ΔV̇E = 48 ± 12%, ΔV̇O2 = 25 ± 11%, p < 0.01). This suggests that changing V̇E itself cannot account for the marked V̇O2 OSC seen in CHF. In the patients, EELV showed no systematic OSC, did not correlate with ΔV̇O2, and was not significantly different from zero. In contrast, in the control subjects, EELV tended to be lower at peak V̇E (-0.14 ± 0.5 L, p = 0.06), and it was well correlated with ΔV̇O2 (r = 0.6, p < 0.01). In conclusion, V̇O2 oscillations in patients with CHF are more prominent than the associated V̇E OSC, are greater than the V̇O2 OSC that can be induced by volitional PB, and are not associated with changes in EELV. This supports the hypothesis that cardiac output OSC contribute to V̇O2 OSC.