A design of experiments methodology was used to investigate the effect of vaporgrown carbon nanofiber (VGCNF) weight fraction, high-shear mixing time, and ultrasonication time on the Izod impact strength of vinyl ester (VE) based nanocomposites. A response surface model (RSM) was developed for predicting impact strengths using a regression analysis approach. The RSM predicts a maximum increase in impact strength of 18% at a VGCNF weight fraction of 0.17 parts per hundred parts resin (phr) (a volume percent of ~0.1) and 100 min high-shear mixing when compared to that of neat VE. The impact strength predictions show an initial increase for low VGCNF weight fractions and extended high-shear mixing. However, a marked decrease in impact strength occurred as the VGCNF weight fraction increased above 0.45 phr. Scanning electron micrographs of the fracture surface of several specimens suggest that the impact strength of VGCNF/VE nanocomposites is directly related to nanofiber dispersion.