We investigated the effects of increases in calf volume on cardiovascular responses during handgrip exercise (HG) and post-handgrip exercise muscle ischemia (PEMI). Seven subjects completed two trials, consisting of one control (no occlusion) and one venous occlusion (VO) session. Both trials included a baseline measurement, followed by 15 min rest (REST), 2 min HG, and 2 min PEMI. VO was applied at a pressure of 100 mmHg via cuffs placed around both distal thighs during REST, HG and PEMI. Mean arterial pressure, heart rate, forearm blood flow in the non-exercised arm (FBF) and forearm vascular resistance in the non-exercised arm (FVR) were measured. During REST and HG, there were no significant differences between trials in all parameters. During PEMI in the control trial, mean arterial pressure and FVR were significantly greater, and FBF was significantly lower than baseline values (P < 0.05 for each). In contrast, in the VO trial, FBF and FVR exhibited different responses than in the control trial. In the VO trial compared with the control trial, FBF was significantly greater (2.5 ± 0.3 and 4.7 ± 0.5 ml/100 ml/min for control and VO trial, respectively, P < 0.05), and FVR was significantly lower (49.1 ± 4.6 and 28.0 ± 4.8 units for control and VO trial, respectively, P < 0.05). These results indicate that increases in vascular resistance in the non-exercised limb induced by activation of the muscle chemoreflex can be attenuated by increases in calf volume.