Factor XIII (FXIII) deficiency is a rare hemorrhagic disorder for which the highest incidence occurs in southeast Iran. The aim of this study was to assess molecular characteristics, clinical manifestations and management of life-threatening diathesis in FXIII deficiency. This study was conducted on 190 patients with FXIII deficiency. Genotype analysis for the most frequent mutation of FXIII-A subunit gene in Iranian, Trp187Arg, was performed for all patients. Clinical manifestations and management of patients with intracranial hemorrhage (ICH), miscarriage and neonates with FXIII deficiency were documented. Neonates were divided in two groups: Group 1 received a standard dose of Fibrogammin P^® (10-26 IU/Kg) and group 2 received a high dose of this drug (60-80 IU/Kg) for 36 months. Bleeding episodes in both groups were recorded, and neonates of group 2 were regularly checked for thrombotic events. Molecular analysis revealed that all patients were homozygous for Trp187Arg mutation. Umbilical bleeding, hematoma and prolonged wound bleeding were common presentations. ICH was another common presentation leading to behavioral and developmental disorders and aphasia. ICH was managed by Fibrogammin P^® at a dose of 10-26 IU/Kg, and miscarriage was managed by Fibrogammin P^® at a dose of 10 IU/Kg every 2 weeks during pregnancy, and the same dose administered as prophylaxis before gestation every 4 weeks. Neonates of group 2 received 60-80 IU/kg dose of Fibrogammin P^®. This higher dose did not trigger thrombotic events but significantly decreased bleeding episodes and prevented the occurrence of major bleeding. Trp187Arg is the most common mutation of FXIII-A subunit in Iran, and Fibrogammin P^® is effective in the management of FXIII deficiency, and higher dose of this drug is safe and effective in neonates.