OBJECTIVES:   To evaluate the cost-effectiveness of the LNG-IUS compared with other therapies for the treatment of heavy menstrual bleeding (HMB) in the United States (US).  METHODS: A microsimulation model examined the five-year treatment experiences of 1,000 hypothetical women with HMB from a US payer perspective.  Women could begin treatment with LNG-IUS, four oral agents (generic combined oral contraceptives (COCs), branded COCs, oral progestogens, or tranexamic acid) or surgery (endometrial ablation or hysterectomy).  Women who failed a non-surgical treatment line could switch to another non-surgical or surgical therapy (up to three non-surgical treatment lines were allowed).  Women who failed all non-surgical treatment lines had the option of surgery as a fourth-line treatment.  Treatment success was defined as menstrual blood loss < 80 milliliters per menstrual cycle (data were obtained from recent literature).  Women could also experience adverse events, unintended pregnancy, or discontinue treatment during any treatment line (probabilities of these events varied by treatment).  Response to treatment was evaluated every three months.  The outcome of interest was cost per hysterectomy avoided.  Robustness of model results was tested in Monte Carlo probabilistic sensitivity analyses. RESULTS: Initiating HMB treatment with LNG-IUS dominated all other strategies: it was the least costly ($1,253 per woman) and resulted in fewer hysterectomies (6 per 1,000 women) compared with the other strategies (costs ranged from $2,291 for generic COCs to $8,219 for hysterectomies; number of hysterectomies per 1,000 women ranged from 9 for ablation to 96 for progestogens).  Two years of treatment with LNG-IUS was less costly and more effective than other treatments, except for ablation, which was more costly but more effective than LNG-IUS.  Sensitivity analyses confirmed these results. CONCLUSIONS: Initiating treatment with LNG-IUS results in fewer hysterectomies and is a cost-saving, or highly cost-efficient, treatment after 5 years for HMB compared with strategies beginning with oral therapies or surgery.