Treatment-related toxicity remains a challenge in pediatric hematopoietic stem cell transplantation (HSCT). In this prospective, single-center study we studied activation of the complement system peri- and post-transplant through plasma C3a and SC5b-9. We also studied acute adverse events and key vascular complications and analyzed their possible relationship to complement activation. Out of 42 patients, 39 (92.9%) had at least one adverse event (grade 2-4) during the first 100 days post-transplant, and 23 (54.8%) at least one severe (grade 3 or 4) event. We identified a total of 4/42 (9.5%) patients with capillary leak syndrome (CLS), veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) or thrombotic microangiopathy (TMA). 50% of the patients with endotheliopathy died of toxicity. Complement activation was assessed in 26 patients. HSCT was accompanied with increases in blood C3a, peri-transplant C3a peaked at 30 min and 24 h. During the first 6 months post-transplant ten patients showed at least a 50% elevation in SC5b-9, but this did not clearly correlate with clinical adverse events. One patient with severe TMA had a significant increase in SC5b-9 peaking at 1-month post-transplant at nearly 40 times the pre-transplant level. Terminal complement activation thus appears to be linked only to clinically significant HSCT-TMA.