Abstract Crashes occurring on rural two-lane highways are more likely to result in severe driver incapacitating injuries and fatalities. In this study, mixed logit models are developed to analyze driver injury severities in single-vehicle (SV) and multi-vehicle (MV) crashes on rural two-lane highways in New Mexico from 2010 to 2011. A series of significant contributing factors in terms of driver behavior, weather conditions, environmental characteristics, roadway geometric features and traffic compositions, are identified and their impacts on injury severities are quantified for these two types of crashes, respectively. Elasticity analyses and transferability tests were conducted to better understand the models’ specification and generality. The research findings indicate that there are significant differences in causal attributes determining driver injury severities between SV and MV crashes. For example, more severe driver injuries and fatalities can be observed in MV crashes when motorcycles or trucks are involved. Dark lighting conditions and dusty weather conditions are found to significantly increase MV crash injury severities. However, SV crashes demonstrate different characteristics influencing driver injury severities. For example, the probability of having severe injury outcomes is higher when vans are identified in SV crashes. Drivers’ overtaking actions will significantly increase SV crash injury severities. Although some common attributes, such as alcohol impaired driving, are significant in both SV and MV crash severity models, their effects on different injury outcomes vary substantially. This study provides a better understanding of similarities and differences in significant contributing factors and their impacts on driver injury severities between SV and MV crashes on rural two-lane highways. It is also helpful to develop cost-effective solutions or appropriate injury prevention strategies for rural SV and MV crashes.