The aim of the present study was to investigate whether a single-compartment (SCM) and a multi-compartment (MCM) venous return model will produce significantly different time-delaying and distortive effects on pulmonary oxygen uptake (V̇o) responses with equal cardiac outputs (Q̇) and muscle oxygen uptake (V̇o) inputs. For each model, 64 data sets were simulated with alternating Q̇ and V̇o kinetics-time constants (τ) ranging from 10 to 80 s-as responses to pseudorandom binary sequence work rate (WR) changes. Kinetic analyses were performed by using cross-correlation functions (CCFs) between WR with V̇o and V̇o. Higher maxima of the CCF courses indicate faster system responses-equal to smaller τ values of the variables of interest (e.g., τV̇o). The models demonstrated a highly significant relationship for the resulting V̇o responses ( r = 0.976, P < 0.001, n = 64). Both models showed significant differences between V̇o and V̇o kinetics for τV̇o ranging from 10 to 30 s ( P < 0.05 each). In addition, a significant difference in V̇o kinetics ( P < 0.05) between the models was observed for very fast V̇o kinetics (τ = 10 s). The combinations of fast Q̇ dynamics and slow V̇o kinetics yield distinct deviations in the resultant V̇o responses compared with V̇o kinetics. Therefore, the venous return models should be used with care and caution if the aim is to infer V̇o by means of V̇o kinetics. Finally, the resultant V̇o responses seem to be complex and most likely unpredictable if no cardiodynamic measurements are available in vivo. NEW & NOTEWORTHY A single-compartment and a multi-compartment venous return model were tested to see whether they result in different pulmonary oxygen uptake (V̇o) kinetics from equal cardiac output and muscle oxygen uptake (V̇o) kinetics. To infer V̇o kinetics by means of V̇o kinetics, both models should only be used for V̇o time constants ranging from 40 to 80 s. The resultant V̇o responses seem to be complex and most likely unpredictable if no cardiodynamic measurements are available.