Occupantless vehicles (OVs) are a proposed application of automated vehicle technology that would deliver goods from merchants to consumers with neither a driver nor passengers onboard. The purpose of this research was to understand and estimate how the increased presence of OVs in the United States fleet may influence crash risk and associated injuries and fatalities. The approach used to estimate potential modifications in crash risk consequences was a counterfactual simulation, where real-world observations were modified as if alternate events had occurred. This analysis leveraged several U.S. national crash databases, along with the Second Strategic Highway Research Program (SHRP 2) Naturalistic Driving Study (NDS) dataset. The analysis required the derivation of parameters that could be used to modify existing crash estimates as OVs enter the fleet in greater numbers. The team estimated benefit parameters pertaining to (1) the crashes that could be ultimately avoided altogether based on the OV’s smaller size, (2) benefits that could be obtained from the improved crashworthiness characteristics of the OV, and (3) benefits due to the lack of occupants in the OV. Results showed that of the 58,852 fatalities in the national databases examined, a full-scale market penetration of OVs was estimated to reduce fatalities by 34,284, a reduction of 58.2%. Most of this reduction (83%) would come from the lack of occupants in the OVs. Similarly, of the 6,615,117 injured persons in the national databases examined, a full-scale penetration of OVs was estimated to reduce injured persons by 4,088,935, a reduction of 61.8%. As was observed for fatalities, most of this reduction (72.1%) would come from the lack of occupants in the OVs. The results of this investigation, however, should not be taken as definitive benefit estimates. There are important assumptions inherent in the parameters that were used, and some of these assumptions may not be immediately realized. Rather, the results are meant to support critical thinking into how innovative technologies such as OVs may offer benefits that transcend the typical approaches used in vehicle safety, including passive and active safety measures.