Many studies have found that females are at higher risk of injury than males in similar crashes. However, vehicle selection and crash characteristics differ by sex. This study was designed to investigate vehicle and crash differences between males and females and the extent to which they may confound estimates for relative injury and fatality risk. Results indicate that crash-involved female drivers were more often driving cars, SUVs and minivans, while males were more often driving pickups. In crashes involving one female and one male driver, the female was more often in side- and rear-struck vehicles and had a median curb weight disadvantage of 104 kg across all crash types. Vehicle differences represented a 75% increase in relative female fatality odds in head-to-head crashes. In terms of injury risk estimation, differences in crush-based delta-V were found to bias results towards overreporting relative risk for females, although this bias has decreased over time. Results demonstrate the importance of accounting for vehicle and crash differences between women and men when seeking to identify relative injury risk. They also stress the need to address vehicle incompatibility in the U.S. vehicle fleet as part of improving outcomes for females.