Unexpected intraoperative bleeding is associated with a reduced availability of crosslinking capacity (provided through factor XIII (FXIII)) per unit of generated thrombin. Furthermore, FXIII deficiency and thrombocytopenia (but not fibrinogen deficiency) are the most prevalent modulators of clot firmness in the immediate postoperative setting. In this study, we therefore evaluated whether levels of FXIII, fibrinogen, or the platelet count influenced the probability of intraoperative red cell transfusions in patients in the operating theatre. This retrospective study was comprised of 1023 patients, which were in need of blood product support in the operating theatre and of which 443 received red cell transfusions. Due to standard operating procedures, FXIII activity, fibrinogen concentration, and platelet count were measured before transfusion took place, but without influencing the decision to transfuse. FXIII deficiency was frequent (50%), as was thrombocytopenia (49%), but not fibrinogen deficiency (9%). FXIII deficiency was associated with a significantly increased probability to receive red cell transfusions (OR 4.58, 95% CI 3.46–6.05) as was thrombocytopenia (OR 1.94, 95% CI 1.47–2.56), but not fibrinogen deficiency (OR 1.09, 95% CI 0.67–1.76). Similar results were seen for cut-off independent evaluations (receiver operating characteristics (ROC) curves, using continuously distributed variables), where the areas under the curves (AUC) of red cell transfusion for FXIII activity was 0.744 (95% CI 0.716–0.770)/0.632 (95% CI 0.601–0.661) for the platelet count, and 0.578 (95% CI 0.547–0.609) for fibrinogen concentration. All AUCs were significantly different from each other (p < 0.0001 and p = 0.0106, respectively), indicating that FXIII activity was a significantly better predictor of red blood cell (RBC) transfusion than platelet count and fibrinogen concentration. These results suggest that pre-transfusion FXIII activity and to a lesser extent the platelet count influence the probability of intraoperative red cell transfusions. Modifying FXIII activity and/or the platelet count might influence the need for downstream red cell transfusion, thus potentially reducing transfusion associated morbidity. This, however, needs confirmation in future studies.