Immune thrombocytopenia (ITP) is a rare platelet disorder that is often persistent or chronic in adults. Patient management is dependent upon physician judgment and patient preference, given both the rarity of the condition and a paucity of high‐quality clinical trial evidence to inform practice guidelines. A systematic literature review was conducted to provide an up‐to‐date summary of studies evaluating the safety and efficacy/effectiveness of therapies used to treat adults with primary ITP in the second‐line setting. Using comprehensive search strings, several medical research databases were queried. Final abstraction was performed on 186 articles. Most (75%) studies were observational in nature; nearly half were conducted in Europe. Splenectomy was the most commonly studied (n=83, 47%), followed by rituximab (n=49, 26%) and the thrombopoietin‐receptor agonists (TPO‐RAs) romiplostim (n=34, 18%) and eltrombopag (n=24, 13%). Twelve prospective, randomized controlled trials (RCTs) with a placebo or standard‐of‐care arm evaluating the safety and efficacy of either rituximab or a TPO‐RA were identified and described in detail. These trials provide important information on the safety and efficacy of these treatments, and in the absence of head‐to‐head data, offer insights on how these therapies compare with one another in treating adult ITP in the second‐line setting. This review confirms that for most second‐line ITP treatment options, there remains a lack of rigorous evidence derived from RCTs, and for many treatments, there is limited evidence of any kind. The need for additional research to guide treatment choices in this setting and greater use of standardized ITP terminology are highlighted. This article is protected by copyright. All rights reserved.