We report two patients (70- and 49-year-old Japanese men) with acute exacerbation of chronic idiopathic thrombocytopenic purpura (ITP) and deep venous thrombosis of the lower extremities. Both were successfully managed with thrombopoietin receptor agonist (TPO-RA) administration. Both had ITP refractory to steroid treatment. Their immature platelet fraction (absolute-IPF) counts were increased and paralleled the platelet recoveries after TPO-RA (eltrombopag and romiplostim, respectively) without progression of thrombosis. Although ITP has recently been evaluated as a thrombophilic disorder, reports on acute exacerbation of ITP with newly diagnosed thrombosis are limited, and the pathophysiology and association between ITP and thrombosis remain to be elucidated. Moreover, the influences of TPO-RA on thrombosis are still controversial. To our knowledge, this is the first case report describing patients with exacerbation of ITP who developed thrombosis and were treated with TPO-RA. The outcomes of our cases underscore the importance of monitoring thrombosis and not delaying the initiation of anticoagulation treatment during the use of TPO-RA.