Background: Ischemia–reperfusion injury is a major contributor to early graft dysfunction after kidney transplantation and is associated with endothelial damage, reflected by circulating soluble thrombomodulin (sTM). This exploratory study aimed to assess very early graft-level changes in renal vein sTM during reperfusion using a paired-kidney design, in which kidneys from the same donor were preserved using different strategies: static cold storage (SCS) and hypothermic machine perfusion (HMP). Methods: Renal vein blood samples were collected intraoperatively at 1 and 30 min after reperfusion. Plasma sTM concentrations were determined using ELISA. Early graft function was monitored during the first 7 days post-transplantation. Results: Cold ischemia time was longer in the HMP group than in the SCS group (20 ± 8 h vs. 13 ± 6 h, p < 0.05). At 1 min post-reperfusion, sTM levels were comparable between groups. In the HMP group, sTM decreased significantly between 1 and 30 min after reperfusion, whereas no change was observed in the SCS group. Between-group differences at either time point did not reach statistical significance. Early renal function parameters improved in both groups, with no significant inter-group differences. No cases of delayed graft function or graft thrombosis occurred. Conclusions: Kidney preservation strategy may modulate very early graft-level endothelial responses during reperfusion, reflected by renal vein sTM dynamics. Although a limited sample size may have reduced the ability to detect between-group differences, very early renal vein sTM measurements may provide insight into ischemia–reperfusion injury. Clinical relevance requires validation in larger studies.