When a bone substitute biomaterial is implanted into the body, the material's surface comes into contact with circulating blood, which results in the formation of a peri-implant hematoma or blood clot. Although hematoma formation is vital for the early bone healing process, knowledge concerning the biomaterial-induced structural properties of blood clots is limited. Here, we report that implantation of beta-tricalcium phosphate (β-TCP) in a bone defect healing model in rats resulted in significantly delayed early bone healing compared to empty controls (natural healing). In vitro studies showed that β-TCP had a profound effect on the overall structure of hematomas, as was observed by fibrin turbidity, scanning electron microscopy (SEM), compaction assays, and fibrinolysis. Under the influence of β-TCP, clot formation had a significantly shortened lag time and there was enhanced lateral fibrin aggregation during the clot polymerization, which resulted in clots composed of thinner fibers. Furthermore, fibrin clots that formed around β-TCP exhibited reduced compaction and increased resistance to fibrinolysis. Together, these results provide a plausible mechanism for how implanted bone-substitute materials may impact the structural properties of the hematoma, thereby altering the early bone healing processes, such as cell infiltration, growth factor release and angiogenesis.