Background: Factor XIII(F13), or fibrin stabilizing factor, is involved in the last stage of blood coagulation. Although F13 is also known to be activated in wound healing after surgery, the association between F13 levels and postoperative complications after surgery remains unknown. In this study, we hypothesized that the F13 levels during perioperative periods may be related to the postoperative complications after esophagectomy in patients with esophageal cancer. Methods: A prospective study has been conducted for patients with esophageal cancer at our institution (UMIN000011658). Preoperative and postoperative (1st, 3rd, 5th, and 7th postoperative days) F13 levels were examined in 73 patients with primary esophageal cancer who underwent transthoracic esophagectomy. We investigated the association of F13 levels with clinicopathological background factors and the postoperative complications after esophagectomy. Results: The average age of the patients who underwent esophagectomy was 64.8 years, and 66 patients (90%) were males. Major postoperative complications included anastomotic leakage (C-D grade ≥ I: 19%), and pneumonia (C-D grade ≥ I: 34%). F13 level in preoperative esophageal cancer patients ranged from 36 to 155% (median 102%). In general, F13 levels markedly decreased after esophagectomy and gradually recovered after the 5th postoperative day. Preoperative and postoperative F13 levels at each point did not correlate with occurrence of any postoperative complications. However, the patients with 35% or more reduction of F13 level in the 1st postoperative day compared to the preoperative F13 level significantly correlated with higher incidence of anastomotic leakage. The incidence of anastomotic leakage of the patients with F13 change≥35% was 27% while that of the patients with F13 change<35% was only 4% (p = 0.013). Conclusions: This study revealed that perioperative decrement of factor XIII may be a promising predictor of anastomotic leakage after esophagectomy in patients with esophageal cancer.