Fibrinogen has been shown to be responsible for most protein-mediated clot strength via thrombelastography. However, factor XIII (FXIII) activity also plays a prominent role in the development of clot strength. Thus, we hypothesized that changes in FXIII activity would significantly increase clot strength. FXIII (0%, 1%, 6.25%, 12.5%, 25%, 50%, and 100% normal activity) was placed in a fixed volume of citrated FXIII-deficient plasma with 1% tissue factor and calcium chloride and underwent thrombelastography for 10 min. We measured the variables reaction time (R; a measurement of clot initiation), alpha (a measure of the rate of clot formation), amplitude (A; a measure of clot strength), and shear elastic modulus (G; a measure of clot strength). FXIII activity significantly decreased R in a pattern of exponential decay (R2 = 0.77; P < 0.001). FXIII activity significantly increased alpha, following a sigmoidal pattern (R2 = 0.88; P < 0.001). Finally, increases in FXIII activity significantly increased A and G in a sigmoidal pattern (R = 0.89; P < 0.001). We concluded that FXHI significantly affects R, alpha, A, and G. Thus, transfusion decision making with protein-mediated thrombelastographic patterns must account for the contribution of both fibrinogen and FXIII.