OBJECTIVES: The EOS 2D/3D X-ray imaging system is a novel technology with potential clinical benefits in the evaluation of orthopaedic conditions.  However, there is no evidence on other benefits in addition to those derived from reductions in the radiation dose. This study aims to evaluate the cost-effectiveness of EOS compared with standard X-ray and highlight some of the typical challenges in the evaluation of diagnostics. METHODS: A model was developed to evaluate the long-term cost-effectiveness of EOS.  Costs were from a health service perspective and outcomes were measured as quality-adjusted life years (QALYs). Threshold analysis was used to establish the necessary size of the additional health benefits and the level of patient throughput needed for EOS to be considered cost-effective. RESULTS: The incremental cost-effectiveness ratio (ICER) of EOS was well above thresholds of £20,000 and £30,000 per additional QALY in all orthopaedic conditions under base-case assumptions.  Patient throughput was a major determinant of cost-effectiveness.  Threshold analysis on patient throughput showed that 17,700 to 27,600 scans per year with EOS, compared with 7,530 scans per year with computed radiography (CR), were needed to achieve an ICER of £20,000 per QALY.  Health benefits over and above lower radiation would need to increase considerably for EOS to be considered cost-effective. CONCLUSIONS: The health benefits estimated from EOS as a result of radiation dose reductions were insufficient to justify the cost of the system. EOS can only be shown to be cost-effective when compared to CR if the utilisation of EOS is assumed to be about twice the utilisation of CR.  EOS highlights some of the difficulties of establishing the relevant care pathway, potential indications, patient benefit from the imaging features, and patient throughput. The evaluation of EOS is an example of how methodological challenges presented by diagnostics can be overcome.