OBJECTIVES: To evaluate the cost-effectiveness of first-line treatment of heavy menstrual Bleeding (HMB) from the perspective of the Spanish National Healthcare System. METHODS: A cost-effectiveness analysis was performed using a Markov model to simulate the evolution of a cohort of women in reproductive age, with HMB and who wish to preserve their fertility status, in a time horizon of 5 years. The treatment strategies were levonorgestrel intrauterine system (LNG-IUS), estradiol valerate/dienogest (E2V/DNG), combined oral contraceptives (COC) and oral progestins (PROG). Clinical data was modelled indirectly combining literature and expert opinion. Outcomes were symptom-free months (SFM), quality-adjusted life months (QALM) and costs expressed in € in 2012. A probabilistic sensitivity analysis was conducted to examine the robustness of the results. RESULTS: The mean treatment cost of HMB at 6 month was 205€ for LNG-IUS, 318€ for E2V/DNG, 412€ COC and 766€ PROG. In the analysis over 5 years, LNG-IUS produced savings of 578€ compared to E2V/DNG, 991€ compared to COC and 1,821€ compared to PROG. Regarding the effectiveness, LNG-IUS provided 51.30 SFM, while E2V/DNG, COC and PROG provided 50.64, 49.09 and 47.77 SFM, respectively. Moreover, 77%, 65%, 56% and 46% of the patients treated with LNG-IUS, E2V/DNG, COC and PROG, respectively, continued treatment without surgery during the 5 year period. Considering QALM as outcome, LNG-IUS and E2V/DNG were the options that yielded more gains in QALM (49.71 for LNG-IUS, 48.09 for E2V/DNG, 46.59 for COC and 44.66 for PROG). LNG-IUS was the most effective and less costly, therefore dominant option. In the oral treatments comparison, E2V/DNG was dominant, providing savings and gains in terms of SFM and QALM. The probabilistic sensitivity analysis on the key parameters confirmed the robustness of the base case. CONCLUSIONS: LNG-IUS is a cost-saving option for the treatment of HMB in Spain. Among oral treatments, E2V/DNG is also a dominant strategy.