The etiology of thrombocytopenia is important in treatment and management of the condition. Most platelet parameters that are routinely analyzed in the diagnostic laboratory have not proven useful in identifying the etiology, while specialized assays suffer from poor standardization and lack of agreement between laboratories. The immature platelet fraction (IPF), which indirectly provides a measure of bone marrow function, is showing promise as a valuable marker of thrombopoietic responses. This study set out determine whether the IPF could effectively identify specific underlying etiologies of thrombocytopenia in a large thrombocytopenic cohort, to allow for quicker, more effective management of the condition. The IPF was analyzed in a large cohort of 637 thrombocytopenic patients and 171 healthy control patients on the Sysmex XN 10 hematology analyzer using the specialized fluorescence optical analysis. The thrombocytopenic patients were divided into six cohorts based on etiology. The IPF% was significantly higher in cases of increased platelet consumption (median = 9.55, min = 1.1, max = 77.9) or pseudothrombocytopenia (median = 13.1, min = 0.4, max = 28.8) compared with control (median = 4.2, min = 1.3, max = 12.8). Furthermore, the IPF% was also able to identify idiopathic thrombocytopenic purpura (ITP) (p < 0.05) (median = 13.4, min = 2.8, max = 77.9) from other causes of increased platelet consumptive disorders (infection: median = 6.4, min = 1.1, max = 21.6; hemorrhage: median = 8.9, min = 1.2, max = 20.2). By use of this large thrombocytopenic cohort, the IPF% has been found to be of significant diagnostic value, providing a useful rapid test in the etiological investigation of platelet disorders.