The changes in blood pressure (BP) and heart rate (HR) during exercise grow with the development of muscle fatigue due to activation of the ergoreflex (ER), which is commonly assessed by post-exercise blood flow occlusion. However, this approach does not reproduce ER functioning in natural conditions and is of little use for testing ER from receptors of lower limb muscles, which differ from upper limb muscles in metabolic characteristics, and are also subject to more pronounced changes as a result of physical inactivity in various diseases. The aim of this study was to compare changes in systemic hemodynamics during “natural” ER activation with the development of severe fatigue in a test with rhythmic static contractions of thigh or forearm muscles until failure to work. Nine young men performed rhythmic isometric contractions of the knee extensors or the wrist flexors while maintaining a given load level (40% of the maximum voluntary effort) in a 20 s contraction/20 relaxation mode until fatigue (work duration in both tests was about 30 min). During the tests, systemic BP (Finapres), stroke volume (SV, ModelFlow algorithm) and ECG were continuously recorded. Rhythmic contractions of both muscle groups were accompanied by an increase in BP and HR, while SV decreased. As fatigue developed, the changes in BP and SV during muscle contraction became more pronounced. Importantly, during contractions of the thigh muscles, fatigue potentiated an increase in BP because of an increase in total peripheral resistance, and during contractions of the forearm muscles, because of an increase in cardiac output. Thus, fatigue of various muscle groups is accompanied by activation of different components of the ER – vascular component during lower limb exercise and cardiac component during upper limb exercise. The results obtained must be considered when developing methods for assessing hemodynamic control in cardiovascular diseases, which are often associated with changes in both skeletal muscles and the functioning of the ergoreflex.