Primary immune thrombocytopenia is an autoimmune bleeding disorder characterized by destruction and impaired production of platelets. The affected patients have an increased risk of bleeding, which could be lethal. Multiple drugs are available; the most commonly used as second-line are Thrombopoietin receptor (TPO-R) agonists and Rituximab. However, choosing the best drug is still under consideration, particularly for all the adverse reactions. We conducted a review of the literature search on PubMed to compare the safety and efficacy of TPO-R agonists and Rituximab. Based on our search, TPO-R agonists are associated with a better platelet response, fewer side effects, and less complications. Further studies are needed to determine possible clinical and therapeutic implications of TPO-R agonists.