Ultra-weak photon emission (UPE) is a general feature of living -biological systems. To gain further insights into the origin of UPE and its physiological significance, the aim of the present study was to investigate the connection between hemodynamics (HD), oxygenation (OX), and UPE. Therefore, during venous and arterial occlusion (VO, AO), changes of UPE and surrogates of HD as well as OX were measured simultaneously using two photomultipliers and near-infrared spectroscopy, respectively. We showed that (1) changes in UPE correlate significantly nonlinearly with changes in oxyhemoglobin (Δ[O(2)Hb]), deoxyhemoglobin (Δ[HHb]), and hemoglobin difference (Δ[HbD] = Δ[O(2)Hb]-Δ[HHb]), indicating a complex association between UPE and tissue HD/OX; (2) UPE decreases significantly during AO but not during VO; (3) UPE increases significantly after AO; and (4) the view that ROS are the source of UPE is generally supported by the present study, although some findings remain unexplained in the context of the theory of ROS-mediated UPE generation. In conclusion, the present study revealed new insights into the interplay between HD, OX, and UPE and opens up new questions that have to be addressed by future studies.