AbstractMajor options for second‐line therapy in adults with chronic immune thrombocytopenia (ITP) include splenectomy, rituximab, and thrombopoietin receptor agonists (TRAs). The American Society of Hematology guidelines recommend rituximab over splenectomy, TRAs over rituximab, and splenectomy or TRAs while noting a lack of evidence on the cost‐effectiveness of these therapies. Using prospective, observational, and meta‐analytic data, we performed the first cost‐effectiveness analysis of second‐line therapies in chronic ITP, from the perspective of the U.S. health system. Over a 20‐year time‐horizon, our six‐strategy Markov model shows that a strategy incorporating early splenectomy, an approach at odds with current guidelines and clinical practice, is the cost‐effective strategy. All four strategies utilizing TRAs in the first or second position cost over $1 million per quality‐adjusted life‐year, as compared to strategies involving early use of splenectomy and rituximab. In a probabilistic sensitivity analysis, early use of splenectomy and rituximab in either order was favored in 100% of 10 000 iterations. The annual cost of TRAs would have to decrease over 80% to begin to become cost‐effective in any early TRA strategy. Our data indicate that effectiveness of early TRA and late TRA strategies is similar with the cost significantly greater with early TRA strategies. Contrary to current practice trends and guidelines, early use of splenectomy and rituximab, rather than TRAs, constitutes cost‐effective treatment in adults with chronic ITP.