OBJECTIVES: To assess the cost-effectiveness of trastuzumab/anastrozole compared to lapatinib/letrozole, anastrazole, and letrozole for the treatment of HER2+/HR+ mBC patients in whom treatment with an aromatase inhibitor is suitable from a UK NHS perspective. METHODS: An area under the curve model based on the TAnDEM (trastuzumab/anastrozole vs anastrozole) and EGF30008 (lapatinib/letrozole vs letrozole) RCTs and the findings of a mixed treatment comparison (MTC) conducted on endocrine treatments in HR+ mBC was developed in Excel. A rank preserving structural failure time (RPSFT) model was utilised to account for the 70% cross-over in TAnDEM. In the base-case no attempt to account for the sizeable additional imbalance in 2nd line chemotherapy was made. The anastrozole PFS and RPSFT-adjusted OS curves from TAnDEM were utilised as a baseline from which to implement the required indirect comparisons under the assumption of an AI ‘class effect’ (as suggested by expert clinical opinion and confirmed by the MTC). The present value of all costs and health outcomes attributable to each treatment option were calculated and the efficiency frontier defined. Extensive deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Anastrozole is dominated by letrozole. Lapatinib/letrozole is extendedly dominated by a combination of letrozole monotherapy and trastuzumab/anastrozole. Trastuzumab/anastrozole produced the most QALYs of all regimens. Trastuzumab/anastrozole and letrozole define the efficiency frontier with a base-case ICER of £54,336/QALY. The use of the utility values derived from EGF30008 caused this ICER to fall to £44,497/QALY. CONCLUSIONS: Lapatinib/letrozole is not a cost-effective use of finite NHS resources at any cost-effectiveness threshold. As no attempt was made to account for the imbalance of 2nd line chemotherapy in TAnDEM (31% in anastrozole vs 8% for trastuzumab/anastrozole) and relatively conservative utility values were used within the model the base-case ICER of trastuzumab/anastrozole Vs letrozole (£54,336/QALY) should be regarded as conservative and the true ICER likely lies below £50,000/QALY gained.