OBJECTIVES: When modeling the cost-effectiveness of treating chronic diseases, analysis usually emphasizes the features of the drugs under comparison. The long time horizons necessary to capture the full costs and benefits of intervention means that cost-effectiveness is determined not only by the properties of these comparators, but also by those of rescue therapies. Unfortunately, the effects of rescue treatment are often neglected, and arguments are frequently proffered that they affect both arms equally. When there are differences in durability, however, this can seriously impact results. For example, a treatment that is more durable will generally be found to be more cost-effective when rescue therapy is expensive or ineffective (or both) than when rescue therapy is cheap or effective. Multiple sclerosis is a chronic disease and the recommended treatment sequence has changed considerably in the last decade. We examine the impact of assumptions regarding the modeled sequence of subsequent treatments on estimated cost-effectiveness of natalizumab versus fingolimod in the second-line treatment of relapsing-remitting multiple sclerosis. In particular, we evaluate how the inclusion of a hypothetical expensive, but ineffective rescue therapy affects estimated cost-effectiveness. METHODS: We used a micro-simulation model that was initially developed to review the cost-effectiveness of multiple sclerosis treatments currently available in Sweden, with a 20-year time horizon and a societal perspective. Costs were sourced from Swedish publications and price lists, and QALYs were based on estimates from a Swedish patient survey. RESULTS: By altering the rescue therapy, estimated cost-effectiveness of natalizumab versus fingolimod switches from around SEK 690,000 per QALY gained to cost-saving (i.e., dominating) versus fingolimod. CONCLUSIONS: The treatment sequences modeled in economic simulation can greatly impact estimated cost-effectiveness. It is important to model the sequence of rescue therapies properly in considering chronic and progressive diseases. Good practice guidelines should be amended to include this more explicitly.