The aim of this study was to identify some of the mechanisms that could be involved in blunted ventilatory response (E) to exercise in the supine (S) position. The contribution of the recruitment of different muscle groups, the activity of the cardiac mechanoreceptors, the level of arterial baroreceptor stimulation, and the hemodynamic effects of gravity on the exercising muscles was analyzed during upright (U) and S exercise. Delayed rise in E and pulmonary gas exchange following an impulselike change in work rate (supramaximal leg cycling at 240 W for 12 s) was measured in seven healthy subjects and six heart transplant patients both in U and S positions. This approach allows study of the relationship between the rise in E and O₂ uptake (O₂) without the confounding effects of contractions of different muscle groups. These responses were compared with those triggered by an impulselike change in work rate produced by the arms, which were positioned at the same level as the heart in S and U positions to separate effects of gravity on postexercising muscles from those on the rest of the body. Despite superimposable O₂ and CO₂ output responses, the delayed E response after leg exercise was significantly lower in the S posture than in the U position for each control subject and cardiac-transplant patient (2.58 ± 0.44 l and 3.52 ± 1.11 l/min, respectively). In contrast, when impulse exercise was performed with the arms, reduction of ventilatory response in the S posture reached, at best, one-third of the deficit after leg exercise and was always associated with a reduction in O₂ of a similar magnitude. We concluded that reduction in E response to exercise in the S position is independent of the types (groups) of muscles recruited and is not critically dependent on afferent signals originating from the heart but seems to rely on some of the effects of gravity on postexercising muscles.