Objective: Motorcycles and mopeds, often referred to as powered 2-wheelers (PTWs), play an important role in personal mobility worldwide. Despite their advantages, including low cost, space occupancy, and fuel efficiency, the risk of sustaining serious or fatal injuries is higher than that for occupants of passenger cars. The development of safety systems specific for PTWs represents a potential way to reduce casualties among riders. With the proliferation of new active and passive safety technologies, the question as to which might offer the most value is important. In this context, a prioritization process was applied to a set of PTW active safety systems to evaluate their applicability to crash scenarios alone and in combination. The systems included in the study were antilock braking (ABS), autonomous emergency braking (AEB), collision warning, curve warning, and curve assist.Methods: With the functional performance of the 5 safety systems established, the relevance of each system to specific crash configurations and vehicle movements defined by a standardized accident classification system used in Victoria, Australia, was rated by 2 independent reviewers, with a third reviewer acting as a moderator where disagreements occurred. Ratings ranged from 1 (definitely not applicable) to 4 (definitely applicable). Using population-based crash data, the number and percentage of crashes that each safety system could potentially influence, or be relevant for, was defined. Applying accepted injury costs permitted the derivation of the societal economic cost of PTW crashes and the potential reductions associated with each safety system given a theoretical crash avoidance effectiveness of 100%.Results: In the 12-year period 2000–2011, 23,955 PTW riders and 1292 pillion passengers were reported to have been involved in a road crash, with over 500 killed and more than 10,000 seriously injured; only 3.5% of riders/pillion passengers were uninjured. The total economic cost associated with these injured riders and pillion passengers was estimated to be AU$11.1 billion (US$7.70 billion; €6.67 billion). The 5 safety systems, as single solutions or in combination, were relevant to 57% of all crashes and to 74% of riders killed. Antilock braking was found to be relevant to the highest number of crashes, with incremental increases in coverage when combined with other safety systems.Conclusions: The findings demonstrate that ABS, alone and in combination with other safety systems, has the potential to mitigate or possibly prevent a high percentage of PTW crashes in the considered setting. Other safety systems can influence different crash scenarios and are also recommended. Given the high cost of motorcycle crashes and the increasing number of PTW safety technologies, the proposed approach can be used to inform the process of selection of the most suitable interventions to improve PTW safety.